The 65-year-old Republican from Tennessee announced his decision on Tuesday. Corker, who was first elected in 2006, said he told people then that he "couldn't imagine serving more than two terms."
"I also believe the most important public service I have to offer our country could well occur over the next 15 months, and I want to be able to do that as thoughtfully and independently as I did the first 10 years and nine months of my Senate career," the senator said in a statement.
The vacancy in Tennessee opens a long-shot opportunity for Democrats in a traditionally red state. Trump easily won the state in last year's presidential election with more than 60 percent of the vote.
GOP Sen. Lamar Alexander and Corker easily won their 2014 and 2012 re-elections, respectively, with more than 60 percent of the vote.
Corker is the chairman of the Senate Foreign Relations Committee. Trump reportedly considered him for secretary of State.