The Democrat who represents central New Jersey's 12th District announced his decision with an email to constituents on Tuesday.
Holt holds a doctorate in physics. Before joining Congress in 1999, he had a career in academia. He ran for the U.S. Senate last year but lost in the primary to Cory Booker.
His retirement ensures major changes in New Jersey's congressional delegation next year.
Democratic Rep. Rob Andrews resigned this month. Republican Rep. Jon Runyan is also not seeking re-election.