Senate Majority Leader Mitch McConnell was the most prominent GOP figure to lament McGahn's eventual departure.
"Don is the most impressive White House Counsel during my time in Washington, and I've known them all," the Kentucky senator said in a statement Wednesday.
"Don's significance to the judiciary, the White House and the nation cannot be overstated, and I look forward to his continued efforts on behalf of our country," McConnell said.
McGahn is widely credited with spearheading the president's rapid appointment of judges to the federal bench, one of the most consequential actions of his presidency.
In a post on Twitter, Sen. Chuck Grassley, the Iowa Republican who chairs the Senate's Judiciary Committee, pleaded with the president to keep McGahn in his role.
"I hope it's not true McGahn is leaving WhiteHouse Counsel. U can't let that happen," he wrote to Trump's Twitter handle.
Grassley's press secretary, George Hartmann, told CNBC later Wednesday that from "Senator Grassley's perspective, there's not been any White House Counsel who has worked so well and so efficiently with the chairman's office and the Senate Judiciary Committee on judges."
"Senator Grassley has appreciated Mr. McGahn's work over the last two years and has considered him integral to the President's record-breaking success on filling judicial vacancies," Hartmann said.
The Judiciary Committee is set to hold a hearing Tuesday on Trump's second nominee to the Supreme Court, Brett Kavanaugh. McGahn pushed Trump to select Kavanaugh as his nominee and has worked to ensure his confirmation.
Sen. Orrin Hatch, R-Utah, the chairman of the Senate's finance committee, said in a statement posted on Twitter that he wished McGahn well.
"Few have played a more critical role than Don McGahn in shaping the federal bench with individuals who understand the proper role of a judge under the Constitution," Hatch said.
AshLee Strong, a spokesperson for Speaker of the House Paul Ryan, R-Wisc., said the Ryan "is grateful for Don's service to our country including his work in the confirmation processes of two Supreme Court nominees."
"We wish him the best as he finishes his service at the White House and transitions to his next chapter," Strong said.