This is based on opinion. Please don't list it on a work's trope example list.
Tear Jerker / Breath of Fire IV
Nina's sister / Cray's betrothed, Princess Elina. Thanks to many nasty experiments, she's been turned into a god-like monster. It's not perfect though, and she's in extreme pain. You start a quest to find the only weapon that can injure gods, and Cray has to mercy kill her. Combined with the Mad Scientist pulling a Karma Houdini and you've got tears and anger. It's even worse when you realize this (probably) is a prequel, where the Mad Scientist perfected his work, and Big Bad IS a god-like monster. It causes quite the Player Punch for people who have sisters in real life that they love dearly. Nina's narration of "I knew that I would never see my sister again" only makes it worse.
Ershin's last stand against the forces of the Empire. Yes, my tin-can friend... That was an appropriate time to laugh.
The massacre of the Chek inhabitants, which drives Ryu to pure rage and unlocks the power of the Kaiser Dragon.
Mami. She's just a simple village girl in the backwater end of the Empire who finds Fou-Lu badly hurt after Yohm tries to kill him and nurses him back to health and takes care of him by claiming he's her cousin Ryong who talks funny. When the Empire finally catches him, Mami helps him escape and admits to him that all she wanted for them was to have a quiet happy life together and Fou-Lu leaves and second guesses doing so, but leaves anyway. Mami is kidnapped by the Empire and brutally tortured to be used in the Carronade to try and kill Fou-Lu and although it fails, Fou-Lu snaps because he's so shocked that the Empire is that desperate and because he realized they used Mami when her bells land next to him. It does not get better from there.
As above, finding out what happened to Elina and her fate.
The massacre of the Chek inhabitants was bad enough in the game, but in the manga adaption, some of the apprentices have warmed up to Ryu a lot and he grows fond of them. Their deaths trigger Ryu's Heroic B.S.O.D. and his breakdown before, during and afterwards is just tragic.