Luck, who turns 30 on Sept. 12, had met with Colts owner Jim Irsay earlier to tell him of the decision.
The Colts played their third preseason game Saturday night in Indianapolis against the Chicago Bears. Luck already had been ruled out of the game because of an ankle injury, but he was seen on the sideline, laughing and conversing with teammates.
After the game, Luck announced his decision during an impromptu 25-minute news conference. He said an official announcement wasn't planned until Sunday afternoon, but he changed course once news broke during the game.
"I've been stuck in this process," Luck said, stopping several times to gather his emotions. "I haven't been able to live the life I want to live. It's taken the joy out of this game ... the only way forward for me is to remove myself from football.
"This is not an easy decision. It's the hardest decision of my life. But it is the right decision for me.''