Besides Odom Jr, other actors exiting the show are Lin-Manuel Miranda and Phillipa Soo, said The Hollywood Reporter.
Odom Jr, 34, played the iconic role of Aaron Burr on the musical that also earned him the best actor in a musical Tony Award earlier this month.
The actor, who previously was best known for his work in Broadway's "Rent" and on TV's "Smash", announced the news in a Facebook Live broadcast on Sunday before Hamilton's matinee performance.
"It has just been the most completely wonderful, totally healing and inspiring experience from beginning to end. I will never forget the people that I've met here. I will never forget all of you."