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Tear Jerker: Diablo III
The death of Deckard Cain at the hands of Maghda. And then the funeral scene.
Stay just a little while longer Cain... I'll listen...
And then there's Leah's own death as her mother Adria uses her as the vessel for Diablo's resurrection in one of the most horrible betrayals of the entire franchise. Especially sad if you've gone through all her conversations and know about her dream of running an inn of her own someday...
Imps are explicitly stated to be demon children and that when hungry their own parents may attempt to eat them and that the reason they travel in packs is for protection. Most of the time they barely even fight you. They even use the same animations and potentially model (save for different textures) as the children in Caldeum.
Mira's final letter to Haedrig after you help him kill her.
There is a kid in Caldeum that runs around playing with his pet bunny. Then a guard kills the bunny.
One of the refugees of Bastion's Keep is a little boy who ends up losing both his parents during the course of Act III. Your final conversation with him in Act III has the poor kid wishing that he was strong enough to protect them. Your protagonist then tells him to use this to become a man strong enough to protect those he loves.
The aftermath of Diablo's resurrection in Bastion's Keep. Nearly every single NPC save for the merchants and your party is either dead or in despair, including the sweet woman and her soldier husband.
The old fat mayor of New Tristram gets one too. After Diablo rises again, you find his corpse with a guard looking over him who comments that he never ran even though he could have. After being yelled at by you and the villagers for fleeing from New Tristram and being called a coward for all of the game, it's a very emotional moment when you realize you finally got through to him when it counted the most.
Kormac's despair upon discovering the Awful Truth of his order, and subsequently his remorse over killing Jondar, wondering if he could have saved him instead.