Caitlin. She lost her husband Ronnie twice. She tries to fill that hole with with the Flash of Earth Two, but he turns out to be completely evil and even puts her in PTSD. And now thanks to Barry's Cosmic Retcon she's slowly turning into Killer Frost. The poor woman is so freaked out that she doesn't tell any of her teammates about it for several episodes, then Cisco spreads the news against Caitlin's wishes in "Shade," causing the situation to spiral further.
Season 1:
Plastique. She can barely touch anyone or anything without making it explode and has Eiling hounding her to try and exploit her powers.
The real Harrison Wells. He was happily living with his wife only to be killed by Eobard Thawne and have his identity taken by him. His good name and life's work is then ruined by Thawne as part of the latter's plans. It doesn't help that even after Season 1, Team Flash still occasionally refers to Eobard Thawne as "Wells." By extension, Tess as well, who was killed by Thawne and had her significance to history swept under the rug, when originally she was evidently an equal part in STAR Labs' success.
Season 2:
Patty when it's revealed to the audience how much pain and anger the former still carries over her father's murder.
Jesse Wells, held prisoner and tortured by Zoom to be used against her father. The scene where Zoom allows her to see Harry for a brief moment before taking her away again is heartbreaking.
Wally West, though of the Jerkass Woobie variety, at least at first. Raised by a single mother in poverty, who then contracts a fatal degenerative disease that they can't afford treatment for, forcing him to become an illegal street racer as a means to pay the medical expenses for. Then, out of nowhere, he finds out that he has a father and sister he was never told about, and his mother intentionally never told him about them, while said father never tried to track her down. He reacts terribly, but it's hard to not feel bad for the kid.
Assuming he wasn't evil himself, Earth-2 Martin Stein is kept in a permanent And I Must Scream situation by Deathstorm, their death at Zoom's hands really being a mercy for him. Knowing Earth-1 Martin Stein, it is hard to think about.
Griffin Grey was going to live happily with his girlfriend, but the powers he got from Thawne's particle accelerator have ruined his life, since every time he uses them he ages quickly. He is no longer recognizable by his former girlfriend and has desperately been seeking a cure to his deadly powers, to no avail.
The man in the iron mask. Held prisoner by Zoom for who knows how long, with his mask preventing him from even speaking, and it sounds as if it gives him difficulty breathing as well. His attempt to get a message across to Jesse and Barry only makes matters worse for him; they fail to understand the message, and Zoom threatens the man into keeping quiet. Finally, despite Barry's promise to come back for him, the man in the iron mask is left behind when his fellow prisoners escape, and he remains at Zoom's (distinct lack of) mercy. The Reveal in the finale makes his situation even worse: he's the real Jay Garrick, whose identity was stolen by Zoom for the sake of Zoom's twisted idea of "playing hero." Once he's freed, however, he seems to have held together fairly well.
Earth 2 Linda Park/Dr. Light is only a villain in the sense that she's a minor criminal that despite having deadly powers, doesn't like hurting people, as shown by her look of horror when she accidentally kills someone. She was brought to Earth 1 against her will by Zoom and lives in fear of him, ultimately choosing to become completely invisible (without clothes) just to avoid him.
Season 3:
Magenta. She's abused by her father, suffering from a severe Split Personality disorder giving her powers, and is used by Dr. Alchemy into committing mass murder for his cause.
Julian as he's forced into becoming Alchemy against his will by Savitar and doesn't even know it until after Barry locks him in the Pipeline during the mid-season finale.
Season 4: Becky Sharpe has had bad luck all her life. She got hit constantly, got a cheating boyfriend, was sexually harassed and then unjustly fired from a job. She earns good luck after her exposure to dark matter, but at the expense of causing bad luck to other people around her. When she was remorseful of robbing a bank and unwittingly harming people of Central City and remained loyal to Barry during his team-up with the captured Bus Metas, she was possessed by Clifford DeVoe in a cruel Heel–Face Door-Slam.
Henry Allen was wrongfully sentenced to life in prison for wife's death, separating him from his son. He takes it all in stride and is happy to just remain in prison while Barry lives his life. When he finally does come back to Barry's life in Season 2, it's just in time for Zoom for snatch him away and kill him right in front of Barry.
Barry takes his father's (alleged) murder of his mother and uses it to motivate him to become a forensic scientist in pursuit of justice, largely because he wants to free his father. His response to getting superpowers is not to angst, but to genuinely appreciate life all the more. Despite his own internal insecurities, he strives to be a genuinely upbeat and kind-hearted young man.
Iris West-Allen has passed through many misfortunes, but she remains a strong, kind character. Her mother abandons her early and his father makes her believe that she died. Later, her first boyfriend Eddie commits suicide to save Team Flash from Thawne. After Barry creates Flashpoint in a moment of provocation, he creates a timeline when a future version of himself plans to kill Iris. One of her friends sacrificed his life by impersonate her and she has to kill the future version to save the present Barry. After that, she has to bear Barry going to the Speed Force to avoid it from collapsing and has to constantly lie about a leave of absence for various months. Her marriage to Barry was interrupted by Nazis and while they finally could make their vows, DeVoe incriminated Barry of murdering him. When she gets to meet her future daughter Nora, she hated her for a while for a decision made by her future self and while they reconcile, she was revealed to work with Thawne, even if with good intentions, and due to that Barry banishes her from the future before he realizes he was too hard on her. Then she and the team learn that Thawne tricked Nora into erasing herself from existence to save his life and she has to see her be Ret-Gone. Then she has to bear the most certainly upcoming death of Barry. After the Crisis on Infinite Earths, she is kidnapped by Eva McCulloch and trapped in a mind damaging dimension where she sees a mirror clone of her stealing her identity and being romantic to Barry.
Harrison Wells of Earth-2, a.k.a. Harry Wells, comes off as arrogant, rude and lacking in empathy since his entrance in Season 2. However, Zoom has kidnapped his daughter and the Heroic BSoD have worsened his social skills. His wife died when his daughter was very young, which made him fear losing people he cares about and be rude to avoid that feeling. He starts getting fond of Team Flash, but Zoom forces him to steal Barry's speed in exchange of Jesse's life. After Zoom is defeated it seems everything will be okay, but his lack of social skills has made him insufferable to a superheroic team he has created in Earth-2. When he gets a balance between mind and heart and he moves back to his Earth, it is destroyed by the Anti-Monitor.
Season 1:
Blackout, who's only evil because his powers killed his friends, disfigured him, and wrecked his mental state. Not only that, but he constantly has to feed on energy and feels perpetual hunger.
Tony Woodward in Episode 7. He may be a huge bully and jerkass, but he didn't deserve to get manipulated by Thawne and then murdered by Blackout like that.
Hartley Rathaway. Child prodigy who was rejected by his parents when he came out as gay, was betrayed by Thawne when he tried to warn him about the dangers of the Particle Accelerator, and was left suffering from constant, chronic pain and deafness as a result of the explosion. He was fairly antisocial beforehand, but its easy to sympathise with the guy.
Shawna Baez tries to broke her boyfriend out of jail who ends up abandoning her. Even after that she can't stop loving him. In "Rogue Air," the captivity appears to have an impact on her sanity.
Season 2:
Killer Frost is quickly established as a cold-blooded killer, but she's clearly as terrified of Zoom as anyone else on Earth-2, and she loses her husband when he gets carried away brutalising the Flash and is murdered by Zoom for it.
King Shark is a Humanoid Abomination introduced trying to eat The Flash, but his powers making unable to live anything even remotely resembling a normal life, to the extent he's likely never been inside a house, eaten a cooked meal,or had any kind of emotional or physical relationship with anyone since he got them,getting knocked out by Harry and captured by ARGUS, only escaping after Barry has closed the breaches and unable to go home to Earth-2 after he's defeated by The Flash and taken back to ARGUS, make it all but impossible not to feel sorry for him. Season 5 reveals that he is a former human that never wanted to become evil. Finally, Grodd's invasion forces him to forego being cured.
Season 3: Savitar, a.k.a. Future Barry Allen. Essentially our main character but the pain and suffering finally became too much for him after his friends shunned him. As a time remnant, he would have known how main Barry is with Iris and would feel all the pain of having lost her in his timeline and the pain of not having her in the new one. Even if he redeemed himself or if he was saved from disappearing, Savitar had no possibility of a manageable life whatsoever. In spite of his actions, he's the only Big Bad so far that Barry has actually felt bad for.
Season 4: Marlize can hardly be called a saint, but given that the once-loving relationship she had with Clifford DeVoe is dead and her husband is drugging her, it is hard not to feel bad about her.
