Trump said in a statement he had accepted Manafort's resignation, but did not offer an explanation for the departure.
It came in a week when Trump has already reshuffled top campaign leaders, effectively demoting Manafort, and has tried to be more disciplined and on message as he seeks to reset his campaign against Democratic rival Hillary Clinton for the Nov. 8 election.
Trump's son, Eric Trump, said unflattering headlines about Manafort were taking a toll.
"I think my father didn't want to be, you know, distracted by, you know, whatever things that, you know, Paul was dealing with," he told Fox News, while also praising Manafort's work for the campaign.
Questions have arisen about Manafort's previous work for the political party of the Kremlin-backed former Ukrainian leader, Viktor Yanukovich.
Another person close to the campaign said Trump had been unhappy with Manafort for a variety of reasons. Manafort, who first joined the campaign in March, had presided over a period in which Trump had formally sealed the Republican presidential nomination after seeing off 16 rivals.
But the New York businessman, who has never held elected office, has also been embroiled in a series of controversies in recent weeks and has lagged Clinton in opinion polls.
Clinton leads Trump by 8 percentage points among likely voters, according to a Reuters/Ipsos opinion poll released on Friday. The Aug. 14-18 online poll showed that Clinton was supported by 42 percent of Americans who are expected to vote, compared with 34 percent for Trump. Some 23 percent would not side with either candidate.
On Wednesday, Trump overhauled his campaign team, hiring the head of conservative website Breitbart News, Stephen Bannon, as chief executive of the campaign in a move that bolstered his combative image. Trump also promoted adviser Kellyanne Conway, a data-driven political analyst, to campaign manager.
In a similar shake-up in June, Manafort took over the running of the campaign after Trump fired Corey Lewandowski as campaign manager. Wednesday's moves meant a reduced role for Manafort, who had been brought in to try to bring a more professional touch but who had struggled to rein in Trump's freewheeling ways.
"This morning Paul Manafort offered, and I accepted, his resignation from the campaign," Trump said in a statement on Friday.
"I am very appreciative for his great work in helping to get us where we are today, and in particular his work guiding us through the delegate and convention process. Paul is a true professional and I wish him the greatest success," Trump said.
Manafort has come under scrutiny over his work with pro-Russian political groups in Ukraine. Earlier on Friday, a Ukrainian lawmaker offered more details of what he said were records of cash payments allocated to Manafort by Yanukovich's party.
Manafort, in a statement earlier this week, has denied any wrongdoing. The allegations about the payments were first made in The New York Times on Monday.
The Clinton campaign has pointed to Manafort's work in Ukraine to add to its criticism of favorable comments that Trump has made about Russian President Vladimir Putin and to sow doubts in voters' minds about whether the Russian government has an unseen hand in the U.S. election. Russian officials have rejected that accusation.
"You can get rid of Manafort, but that doesn't end the odd bromance Trump has with Putin," Robby Mook, Clinton's campaign manager, said in a statement.
'TOO MANY COOKS'
John Feehery, a Republican strategist, said it would have been unsustainable for Manafort to stay on after Wednesday's hires.
"Too many cooks in the kitchen," Feehery said. "And the Ukrainian stuff was becoming a real distraction."
Although the hiring of Bannon was taken as a signal that Trump would not hold back in his aggressive, unorthodox campaign manner, Trump offered rare words of regret on Thursday for causing offense with his take-no-prisoners style.
Reading from a teleprompter, he told supporters in North Carolina that he had sometimes misspoken. "I regret it," he said, "particularly where it may have caused personal pain."
In recent days, Trump's son-in-law, Jared Kushner, had been searching for someone to join the campaign whom both he and Trump could agree was trustworthy, according to a person close to the campaign. Both had grown uncomfortable with Manafort, the person said.
A spokesman for Kushner declined to comment.
Karlyn Bowman, a senior fellow and research coordinator at the American Enterprise Institute think tank, said Trump still had some time to turn around his campaign, noting the news came as many Americans were enjoying summer vacations.
The final stretch of the protracted campaign traditionally starts after Labor Day, which falls on Sept. 5 this year.
"I'm not sure the public pays a lot of attention to inside campaign stories," she said. "But that said, Trump has clearly been having significant problems in the polls and he needed to do something differently and perhaps this is the beginning of the attempt."