Karam is a story of a Hitman seeking for his Salvation. John (John Abraham) is an assassin working for a mobster named Captain. A turning point happens when John massacres an entire family as he stares into the eyes of a girl who is dying, and decides to quit his life as a Hitman. He starts a fresh life with his wife Shalini. Mean time John's boss, Captain is facing a threat from a rival don Yunus.

After an attack on him, he decides to teach the city a lesson by killing City's top industrialist, top film producer, the cop backing Yunus and lastly Yunus himself; so that everyone else falls in line and no one dreams of becoming another Yunus. And the only one who can make this happen was John, but he is the man who has sworn never to pick up his gun again.

For making the plan works Captain takes away John's love his wife and holds her hostage; in return he has to kill five targets in next 36 hours. Things get worse when city's toughest cop Wagh trace John. In a game of hunter and hunted, allegiances are formed to be broken, friends turn foes and body count begins to grow