The Binding of Isaac is a series of video games created by Edmund McMillen and developed/published by NICALiS about a young boy who jumps into the basement of his house, fighting terrible monsters and wandering through sprawling subterranean dungeons, with multiple endings based on the path the player takes. The core gameplay is a top-down arcadey shooter with permadeath and roguelite elements, collectible items and powerups that the player must find by exploring dungeons similarly structured to the dungeons of the original Legend of Zelda NES game from 1986. The game(s) have many mature themes, including abuse, childhood neglect, death, suicide, as well as heavy religious themes and many references to Christianity, though it would be a mistake to call it a "Christian game" since these themes center more around the ill effects religious zealotry can have on a family.

The first game in the series, simply titled The Binding of Isaac, was an indie flash game originating from Newgrounds. The story of the original game is about a boy and his mother who live together in a small house on a hill. The boy, Isaac, has a great imagination, drawing pictures while his mother watches Christian-based TV shows. Isaac's mother hears a voice, which commands her to strip Isaac of his belongings, lock him in his room, and finally "sacrifice" him. Isaac manages to find "a trapdoor, hidden under his rug", not hesitating to dive down into the basement so he can escape his mother before she takes a knife to him. This is where gameplay begins, with Isaac waking up in his basement and exploring different rooms, trying to find items that can help him defeat progressively stronger and faster enemies as he descends lower and lower into caverns, depths, and other strange environments in a replayable "roguelite" gameplay loop. The success of this first game is often credited as bringing about the "roguelite" genre, with many successful games following it borrowing some of its mechanics like permadeath, randomly generated dungeons or levels with randomly generated items and powerups, and challenging enemies or bosses that take many tries to learn how to defeat.

In 2014, after a long period of development, Edmund McMillen and NICALiS released a total remake and overhaul of the original flash game titled The Binding of Isaac: Rebirth. The core gameplay and story were almost totally unchanged, but with many improvements, new items, enemies, dungeons, and more. Edmund McMillen was dissatisfied with Flash and its limitations for game development, and abandoned it in favor of a homemade C++ based engine while developing Rebirth. Since release, Rebirth has received many content updates and three expansions, as well as overwhelming acclaim from critics and gamers alike, often touted as one of if not the best game in the roguelite genre it helped to popularize.

There have been a few spin-off games to the series, including a tabletop card game, titledThe Binding of Isaac: Four Souls, and a deck-building turn-based strategy game released in 2019, The Legend of Bum-Bo.