Pruitt had become a constant source of embarrassment to a president who had entered Washington promising to "Drain the Swamp."
Pruitt has faced an array of ethical questions about his travel spending, security costs, dealings with industry lobbyists and misuse of government resources.
He had denied wrongdoing in the face of multiple congressional and oversight inquiries.
Despite the scandals, Trump has been approving of Pruitt's efforts to reduce regulations that the administration says curb business growth. Trump writes on Twitter, "Within the Agency Scott has done an outstanding job."
Activists have argued those cuts have endangered the environment.
Trump tweets that Deputy Administrator Andrew Wheeler will assume the acting administrator position Monday.
Wheeler is a former coal industry lobbyist. The Senate confirmed Wheeler as the agency's deputy administrator in April.
Trump tweeted that he has "no doubt that Andy will continue on with our great and lasting EPA agenda. We have made tremendous progress and the future of the EPA is very bright!"
Wheeler, 53, could serve more than a year in an acting role. A Senate vote would be required if he is nominated to lead the agency permanently.
Republicans say Wheeler is well-qualified to lead the EPA, having worked at the agency early in his career. He also was a top aide at the Senate Environment Committee before becoming a lobbyist nine years ago.
Like Pruitt, Wheeler is a conservative who will seek to roll back what some see as excessive air and water regulation.
But unlike Pruitt, Wheeler is considered low-key and is a Washington insider who has spent much of his career in the nation's capital.
Pruitt, a former Oklahoma attorney general, is often aligned with the oil and gas industry, while Wheeler has focused more on coal since becoming a lobbyist a decade ago.
An Ohio native, Wheeler served as a special assistant in the EPA's Pollution Prevention and Toxics office in the early 1990s before moving over to the Senate environment panel, where he eventually became GOP staff director under Sen. Jim Inhofe, R-Okla., the panel's former chairman and Pruitt's political mentor.
Inhofe hailed Wheeler's ascension to EPA chief. "Andrew worked for me for 14 years, has an impeccable reputation and has the experience to be a strong leader at the EPA," he said.
Until his nomination by Trump last fall, Wheeler worked as a lobbyist with a client list that included Murray Energy, one of the nation's largest coal mining companies. He accompanied Murray CEO Bob Murray during a series of closed-door meetings to lobby the Trump administration to kill environmental regulations affecting coal mines.
"Andrew Wheeler's coal credentials are without equal. He is, without question, a member of the coal industry's Hall of Fame," said Sen. Edward Markey, D-Mass. By elevating Wheeler to replace Pruitt, he said, "the EPA is only trading one fossil fuel friend for another."
Markey vowed to fight against Wheeler and said, "The future of our public lands, our waterways and oceans and the very health of the entire planet rest on the continued action of all Americans to take back the EPA from Big Oil and King Coal."
Wheeler was confirmed, 53-45, despite opposition from Markey and other Democrats. Three moderate Democrats - Heidi Heitkamp of North Dakota, Joe Donnelly of Indiana and Joe Manchin of West Virginia - joined with Republicans to support Wheeler in April. All three face tough re-elections in states Trump won easily last fall.
Sen. Tom Udall, D-N.M., called Wheeler a "climate denier" who "has spent much of his political career lobbying for the big polluters EPA regulates."
Widespread disgust for Pruitt "should serve as a blaring red siren for the Trump administration," Udall said. "Americans will not tolerate another EPA administrator whose primary goal is to fight the core mission of the EPA."