In many isekai anime, characters are thrust into incredibly painful situations.
Isekai anime are dramatic as characters overcome every obstacle and live happily ever after. However, not every story ends well. Sad moments in isekai anime are particularly impactful as they involve a hero adapting to a new world after leaving the old one. Therefore, the character's reaction can be greatly influenced.

10. Hajime betrayed by classmates (Arifureta: From Commonplace To World’s Strongest)
Hajime is an ordinary student transported to another world. What's peculiar is that his classmates also end up in this world. In fact, Hajime receives the most ordinary abilities, unlike his classmates.

While in a dark dungeon, he is betrayed by his classmates and pushed off a bridge, falling into the abyss. Hajime doesn't give up trying to escape the dungeon, but loses his hand in the attempt. Worse still, he's forced to eat poisonous creatures in the dungeon when hungry.
9. Rem Galleu harbors a demon king within (How Not To Summon A Demon Lord)
Rem has harbored the demon king since childhood, a curse that haunts her every thought. The prospect of its release terrifies her, a secret she dare not share. She lives each day in fear.

Fortunately, Diablo stands by her side, proudly declaring he vanquished the demon king for her. His words pierce Rem's heart, leaving her in tears for hours.
8. Loyal assassin targeted by his own organization (The World’s Finest Assassin Gets Reincarnated in Another World As An Aristocrat)
Lugh, the top assassin, faithfully served his organization in his past life. Even in old age, he never questioned orders, always completing his tasks flawlessly. He trained the younger generation and shared his experiences with his colleagues.

As time passed, the organization grew wary of him. Lugh boarded a plane that was sabotaged, leaving him no chance of escape. He departed with regret, having dedicated his entire life to this organization.
7. Rudeus abandoned by his beloved (Mushoku Tensei: Jobless Reincarnation)
After Eris ended her relationship with Rudeus Greyrat, he felt happier than ever before, loving her with all his heart. Upon waking up the next morning, he received a letter from his lover, stating they were incompatible.

Rudeus fell into despair. Heartbroken, he couldn't leave his bed for a long time. He suffered from psychological illness and set out alone to heal. Unbeknownst to him, Eris truly loved him and deemed herself unworthy of him. She went to study swordsmanship with a master.
6. Shizue's profoundly moving final moments (That Time I Got Reincarnated As A Slime)
After years of living, Shizue could no longer contain the demon within her. However, before her death, she wished to do something to harm the demon lord Leon, for he had turned her life into a living hell on earth.

Lying on her deathbed, with only Rimuru by her side, Shizue revealed the immense suffering she endured throughout her life, and the fear of demon lord Leon since she was a child, as he destroyed everything she loved.