- Maude's death is one of the first in the series, but Loren's last words to her as she dies drive it in deep.Loren: Maude... Don't go...
- Worse, it was a downhill battle and Loren was an angsty, easily-pissed off shop owner who hates strangers. He got in the way of Dr. Mike properly treating his wife and diagnosing her illness earlier. When it became apparent that Maude was suffering from heart failure, she ordered digitalis powder to delay the onset, but eventually the supply ran out and Maude finally had a fatal heart attack in the store, with Mike and Loren and company helpless to do anything but watch. Up until then, Mike did well to bear the aches and pains of moving out to Colorado Springs. This incident sends Mike into a fit of tears. It's the first time she feels truly broken and doubts her abilities.
- The reveal that Hank has a mentally disabled son. Worse, he had a past love and sired a child through her, but the mother died. However, in exchange for being autistic, the boy is also a savant who can draw like no other. He sketches a picture of the late woman that is a perfect likeness, and Hank had nothing but the memories to remember her by. Upon seeing this photo, he sheds tears for the first and perhaps only time on-screen.
- Jake being forced to relinquish his treasured keepsake of his father, a silver pocketwatch, as part of the reparations to the family of the Cheyenne he accidentally killed. Sully's response to his objection to give it up is even harder to swallow because of how sobering and pitiless it is. It takes on a level of Dramatic Irony upon learning Jake's father ran out on the family when he was little.Jake: My pa gave me this.
- The appearance of Abigail's ghost in "Halloween". Before she bids Mike farewell, Mike is brought to tears, saying that if she knew Abigail in life, they could have become really good friends.
- During a town council meeting to decide if a new teacher who uses corporal punishment should be dismissed or not, Loren is firmly in the camp of supports. However, Jake sits through the meeting with an eerily silent and angry look on his face. Then, it comes up that she is using a belt on the kids, and he becomes even more discontent. Eventually, he just walks out. Then, when Loren comes over to his barber shop, he finds Jake holed away and unwilling to talk to anyone, totally in a stew. Jake then tells him that he was subjected to hellish belt beatings by his own mother as a boy. The gist of it is she was a violent and abusive alcoholic and Jake never knew when she would use it... what would set her off...Loren: I've seen you beat up lots of people before.Jake: DID YOU!?!(goes over to a belt rack on the wall, grabs a belt, then walks up to Loren face-to-face with the offending belt firmly clenched in his hand)Jake: My mother... kept one of these on a ten-penny nail. It hung there like a loaded gun.
Jake: The only thing these things are good for is sharpening knives.
- You can actually hear the rage coursing all through his voice as he describes his hatred of belts.
- There's also Brian's reaction to the teacher beating all his friends and feeling helpless to stop her.
- Dorothy's very disturbing insight that if an adult is being hurt, they can fight back or run away, but that a child can't do either.
- Hank's breakdown following Myra's refusal of his love. Myra was his favorite among the saloon girls, but Horace fell in love with her and she decided she wanted to leave. After a lot of friction back and forth between the three of them, Hank begrudgingly agrees to terminate her employment contract (twice, undoing the first termination to keep another young girl from unwittingly falling into a contract just like she did by taking her place) and throws her things out into the street. He gets drunk and threatens to blow her head off, then gets badly concussed and falls into a coma... right after Horace wishes he was dead. Thankfully, Hank recovers and reforms, but he's still very sore about Myra's departure from his saloon. It isn't until her wedding day with Horace that he finally comes to terms with it, and even when he shows up to politely watch the ceremony, everyone's leery of him for good reason after what he did earlier, fearing that he's come to crash the festivities.
- The reveal in Season 3 that Olive died off-screen from fever because her telegram came too late to get help in time, all because she chose to move out far west in the first place. With her death, Loren has no blood family left in the world at all.
- Mike's Trauma Button being pushed when she encounters a patient who suffered the same kind of brain aneurysm that suddenly killed her father. She later explains the circumstances of her father's death: he was eating breakfast and talking and acting just fine, but then out of nowhere, slumped down in his food and was dead instantly. Adult Fear rings out extremely hard with this, because there were no warning signs it was coming except the stress of his job, and the idea that someone close to oneself could just up and die without warning is very haunting, to say the least.
- "Washita", full stop. If you thought the Cheyenne kept having it bad till now, they can't hold a candle to this one. The whole Cheyenne tribe is massacred, Black Kettle and company included, Cloud Dancing loses his wife (cutting his flesh to perform a ritual bloodletting and a piece of hair to bury with her so her soul may find rest, hearkening back to a previous episode where Jake shot a Cheyenne), and Mike has a Heroic BSoD that results in her locking herself in her barn, wrecking up a few things, and finally collapsing in a broken heap, wailing inconsolably.
- Loren's prejudice towards Jewish people because his father was put out of business and subsequently ruined by his Jewish competitor leads him to take out his frustrations on another Jewish salesman who arrives in Colorado Springs and he perceives to be threatening his business, painting him as a threat to the town. Unfortunately, the townspeople get drunk and tip over his business carriage, and the man gets pinned underneath trying to stop them, considerably injured. To twist the knife deeper, this is right around Christmastime. Loren realizes he's the reason why this happened and tries to make amends.
- "Brother's Keeper" employed the Cartwright Curse to full effect after the series saw three weddings go off without a hitch, and killed off somebody very innocent. Ingrid. Her death is a huge, huge blow. One of the sweetest and most lovable characters gets bitten by a rabid Pup, and Mike can't detox her. She has an agonizing death to rabies, screaming manically, and Matthew loses his future wife in the process, all his plans to start a family on a homestead of his own smashed to bits. He still managed to spiritually marry Ingrid before she went, with God as their witness. Hearing Ingrid declare she would be Matthew's wife forever in a final lucid moment is a kick in the teeth. Then he just crumbles in the wake following her funeral and causes Colleen to burst into tears.
- Brian also suffers a huge loss off his own when Pup, the beloved wolf he's had at his side from the very first episode since Sully gifted the animal to him as a puppy, now has to be put down to avoid killing anyone else with rabies all because a rabid racoon ticked him off and fought back when Pup jumped it (which dies from its own infection). Pup was so strong he outlasted Ingrid after contracting rabies, and Brian only set out to put him down to appease a bereaved Matthew. However, he couldn't bring himself to finish the deed. Then Matthew arrived in pursuit of Brian and girded himself with the hunting rifle Brian took from the house, but then he couldn't do it, either. Only when Sully arrived did Pup's demise come to fruition, and Sully, who went out and got Pup for Brian special those several years ago, has to close his eyes while taking the shot, and Matthew shields Brian from viewing the tragedy while closing his own eyes. The episode ends with both of them crying and cradling each other in total, unbridled grief. Just brutal.
- Even after Ingrid's burial, Matthew is in shock to the point of losing himself. Matthew's delayed reaction to her death is even worse, a slow-burning grief finally culminating in "Hell on Wheels" when he tries to kill himself with explosives. When he talks about her death for the first time in front of Mike and Sully, he opens a music box which plays the song they danced to at the hurdy-gurdy dance... and then he breaks down sobbing. He finds release when he sets a Chinese Lantern out to sea and the light goes out, indicating her soul has passed on to the afterlife and found rest.Matthew: Goodbye... Ingrid.
- Even worse, the person who organized the hurdy-gurdy dance is also dead. Foreshadowing if there ever was any.
- The realistic portrayal of Horace and Myra's collapsing marriage in Season 4, all because they aren't honest and more forgiving with each other and trying to fit into societal roles instead, when they really should be breaking free of them for the sake of their love. It starts off with petty arguments and the couple going to bed bitter, then accelerates to Horace disapproving of Myra's wild ideas and wanting her to be a more traditional housewife, then escalates further to Horace taking the stresses of his telegraph office job out on his wife, the Myra acting rebellious to spite Horace and getting a job as a bank teller, followed by a temporary mutual apology that only serves to slap a band-aid on a much bigger crack forming in their relationship. The whole thing finally crumbles when Myra causes a scene at a controversial opening ceremony for Preston's inn, Hank mocks her, and Horace gets in a vicious fight with Hank. Myra sees the ugly side of Horace's personality has overshadowed the nice qualities, and Horace, feeling guilty for letting his temper blow like that and withdraws emotionally, causing Myra to feel so alienated that she feels a need to have some time away from her husband. The two reluctantly agree to separate, and Myra takes a train to go live with relatives until the hard feelings blow over... however, because they never worked out their differences when they could have, Myra resists coming back, and the two decide to divorce entirely, unable to work out these issues at this stage.
- Jake bursting into tears as he describes the epitaph he wants on his father's grave.
- When Myra and Horace about to finalize their divorce, he falls into severe depression, swigs down a ton of pills in an attempt to kill himself. When Myra hears this, she bolts to Colorado Springs with their daughter Samantha and aborts the divorce entirely.
- Dr. Mike being forced to fumigate and cremate her entire clinic in "A Place to Die", because somehow, it has developed a staph infection- something that was yet to be discovered and properly identified as a malady in her time. For all she knew, her clinic was tainted, and everything was toxic, forcing her to burn her entire collection of medical records, equipment, furniture, her framed license to practice, and even keepsakes that she could never replace, like a treasured photo of her family that was so significant it used the establishing shot of the very first scene of the series. The whole town came out to watch her burn up her paraphernalia like a funeral pyre in sorrow, and Mike sat there crying silently.
- Reverend Timothy Allen going blind due to a sudden, unexpected problem with his eyesight that gradually and irreversibly worsens into total vision loss.
- Mike's miscarriage. She can't bring herself to tell Sully after it happens because she's afraid of how he'll react to the news, and holds off until Dorothy finally encourages her to confide the truth to him.
- The epidemic in the final season serves to kill off three major characters. One of them happens to be Anthony, but he doesn't die right off the bat. Anthony, who is already an Ill Boy who was at risk of dying at any time without warning, dies as a result of kidney failure brought on by exposure to the epidemic, which sealed his fate. Losing him nearly destroys Robert E and Grace's marriage when they both just shut down and stop communicating to each other, which causes Robert E to ultimately take his grievances out on a professional boxer.
- The other two are Dr. Mike's own sister, Marjorie (the crabby one who Loren got romantically involved with) and Coleen's best friend, Becky, which devastates her.
- The death of Michaela's mother in the Grand Finale. It creates Book-Ends to the death of her father at the very start of the series.
Tear Jerker / Dr. Quinn, Medicine Woman