Sen. Bob Corker of Tennessee, chairman of the influential Foreign Relations Committee, will not seek re-election in 2018.
He is the first senator to announce retirement plans ahead of next year's election cycle.
"I also believe the most important public service I have to offer our country could well occur over the next 15 months," Corker said in a statement, "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."
That could well be an allusion that Corker may speak out more in areas where he may disagree with President Trump.
Corker also hinted that his political career may not be over.
"I know that we will continue to have an impact for the remainder of our term," Corker said, "and I look forward to finding other ways to make a difference in the future."
Corker, 65, the former mayor of Chattanooga, Tenn., has been a steadfast conservative in his votes but moderate in his tone, from making a mark on the auto bailout to playing a key role in the consideration of authorization of force in Syria during the Obama administration.
He embraced Trump during the campaign and was even said to be in the running for secretary of state before the job instead went to former Exxon Mobil CEO Rex Tillerson.
But Corker's relationship with the president has soured somewhat. In May, he referred to the administration as being in a "downward spiral" that Trump needed to get "under control."
He also said in August he believed the president "has not yet been able to demonstrate the stability, nor some of the competence that he needs to demonstrate in order to be successful."
Former White House chief strategist Steve Bannon had threatened to field a primary opponent to Corker.
Even before Corker's comments, polls showed that many conservative voters were unhappy with him. And since then, their attacks on the senator have intensified.
His departure opens the door for other GOP candidates.
One Republican considering running is Mark Green, a doctor and state lawmaker. Earlier this year, Green was Trump's pick to be Army secretary but withdrew from consideration after being criticized by LGBT and Muslim rights organizations.
Here's his full statement:
"After much thought, consideration and family discussion over the past year, Elizabeth and I have decided that I will leave the United States Senate when my term expires at the end of 2018.
"When I ran for the Senate in 2006, I told people that I couldn't imagine serving for more than two terms. Understandably, as we have gained influence, that decision has become more difficult. But I have always been drawn to the citizen legislator model, and while I realize it is not for everyone, I believe with the kind of service I provide, it is the right one for me.
"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.
"Serving the people of Tennessee in this capacity has been the greatest privilege of my life. And as I spent the month of August traveling across our great state, I was reminded that we live in a unique place full of people who care deeply about the direction of our country.
"I am grateful to the people of Tennessee for the opportunity to serve my state and country. I have been fortunate to do so with an extraordinary staff, and I want to thank them for their incredible dedication. I know that we will continue to have an impact for the remainder of our term, and I look forward to finding other ways to make a difference in the future.
"Finally, I want to thank my wife, Elizabeth, and our family, who have made many sacrifices in allowing me to serve. Nothing I have done would have been possible without their love and support."
Chas Sisk is a reporter for NPR member station WPLN in Nashville, Tenn.