"I am troubled by the timing and reasoning of Director Comey's termination," Senate Intelligence Chairman Richard Burr, a North Carolina Republican, said in a statement.
While Democrats slammed Trump's decision on Comey as "Nixonian,"
some members of the President's own party expressed concerns and divided traditional GOP alliances.
Arizona Sen. John McCain said he was "disappointed" by the incident. Sen. Bob Corker, who chairs the Senate Foreign Relations Committee and occasionally advised the Trump campaign last year, said he also had concerns.
"Regardless of how you think Director Comey handled the unprecedented complexities of the 2016 election cycle, the timing of this firing is very troubling," said Sen. Ben Sasse of Nebraska in a statement.
Rep. Justin Amash, a member of the conservative House Freedom Caucus, said in a tweet that he would introduce legislation supporting the creation of an independent commission to investigate Russia's interference in the election.
Amash is one of four Republicans who have signed on to legislation that would force Trump to release his tax returns.
"While the case for removal of Federal Bureau of Investigation Director James Comey laid out by Deputy Attorney General Rod J. Rosenstein was thorough, his removal at this particular time will raise questions," Corker said in a statement. "It is essential that ongoing investigations are fulsome and free of political interference until their completion, and it is imperative that President Trump nominate a well-respected and qualified individual to lead the bureau at this critical time."
Other Republicans came to Trump's defense or placed the blame for Comey's firing squarely on the shoulders of the former FBI director.
House Speaker Paul Ryan, in an interview with Fox News' Bret Baier on Wednesday, said Comey was "compromised" and supported Trump's decision.
"I think the truth is James Comey, who is a worthwhile and dedicated public servant, I think he had just basically lost the confidence of a lot of Republicans and a lot of Democrats," Ryan said. "Most importantly, he lost the confidence of the President, and it is entirely within the President's role and authority to relieve him."
Ryan also dismissed calls for an special counsel or independent investigation into potential collusion between the Trump campaign and Russia.
"I think the intelligence committees are the ones that should do this," Ryan said.
"Today's announcement is likely the inevitable conclusion of Director Comey's decision last July to bypass the longstanding protocols of the Justice Department and publicly announce the reasons he had decided not to recommend an indictment of Hillary Clinton and to offer his personal views of Mrs. Clinton's actions," Republican Sen. Susan Collins said in a statement.
"Any suggestion that today's announcement is somehow an effort to stop the FBI's investigation of Russia's attempt to influence the election last fall is misplaced," Collins said. "The President did not fire the entire FBI; he fired the director."
The decision also had two traditional Republican allies apparently at odds. While McCain said Comey is "a man of honor and integrity, and he has led the FBI well in extraordinary circumstances," one of his closest friends -- Sen. Lindsey Graham -- said that he disagreed.
The South Carolina Republican, who is leading one of four investigations into Russia's interference in the 2016 election, said Tuesday he supports Trump's decision.
"Given the recent controversies surrounding the director, I believe a fresh start will serve the FBI and the nation well," Graham said in a statement Tuesday. "I encourage the President to select the most qualified professional available who will serve our nation's interests."
Republican Sen. Marco Rubio said he was not commenting on the firing specifically but expected the Justice Department's investigation to continue largely unchanged.
"I would expect the FBI to continue to function along the lines that we have come to expect it to function," the Florida Republican told CNN.
Sen. Jeff Flake, a Republican who's up for re-election next year, tweeted that he couldn't explain Trump's decision.
, "I've spent the last several hours trying to find an acceptable rationale for the timing of Comey's firing. I just can't do it."