This is based on opinion. Please don't list it on a work's trope example list.
Tearjerker / My Name Is Earl
The scene where Earl is in a coma and his condition is failing. In fact, as evidenced by being almostPut on a Bus in the Dom Com playing in his head, he actually is dying. And Randy is talking to him while Bob Dylan 's "Knockin' On Heaven's Door" plays in the background.
It's hard to feel sorry for Joy, but two episodes might get you a little misty. In one, she's losing her dreams of fame as "Reflections" (Diana Ross) plays on the soundtrack. In the other, she's watching her kids play at a function where she's not invited, while Bob Dylan's "Just Like a Woman" plays. She asks Earl if she's a bad mother and sounds utterly defeated.
In Gospel Reverend Green's faith in god is shaken throughout the episode to a point where he breaks down and returns to his criminal lifestyle. This impacts people who have gone through similar experiences of redemption but only to be mistreated enough by others to a point where they return to their former way life.
Earl's reaction to seeing Earl Jr. in "Guess Who's Coming Out of Joy" counts, even more so since up to that point, he was incredibly excited about having his own son.
The sequence with Earl taking the fall for Joy and going to jail at the end of season 2 is thoroughly depressing. The commentary points out one particularly sad moment: when Earl is led off, Randy instinctively follows him only to be sent back.
Perhaps the saddest moment is seeing his supervisor at the warehouse proclaim, "Always a docker". Earl spent an entire episode working like a dog to earn respect and shake the image of a docker, and then it goes up in smoke and it isn't even his fault. And he gets blamed for it anyway, presumably fired, and it becomes All for Nothing.