The final vote to confirm retired Marine Gen. James Mattis to run the Department of Defense was 98-1. New York Democratic Sen. Kirsten Gillibrand was the only senator to vote against him, with Alabama Republican Sen. Jeff Sessions -- Trump's pick for attorney general -- abstaining.
Retired Marine Gen. John Kelly similarly sailed through for Homeland Security, though he had more detractors. He was confirmed 88-11.
The Senate will not consider Kansas Rep. Mike Pompeo for CIA director until Monday, after at least three Democrats objected to his quick confirmation over concerns including surveillance. Instead, they voted on opening debate on his nomination, a procedural step.
"I am pleased by the confirmation votes of Generals Mattis and Kelly. These uniquely qualified leaders will immediately begin the important work of rebuilding our military, defending our nation and securing our borders. I am proud to have these two American heroes join my administration," Trump said in a White House statement, his first since becoming President.
"I call on members of the Senate to fulfill their constitutional obligation and swiftly confirm the remainder of my highly qualified cabinet nominees, so that we can get to work on behalf of the American people without further delay."
Later Friday night, Trump signed papers confirming Mattis and Kelly's appointments, and both were sworn in by Vice President Mike Pence.
In a statement to the Department of Defense Friday night, Mattis pointedly praised the intelligence community, saying that along with the Pentagon, they are "the sentinels and guardians of our nation." He also vowed to "work with the State Department to strengthen our alliances."
The comments were notable in their contrast to public positions taken by Trump, most notably his skepticism of the intelligence community's increasing belief that Russia meddled in the 2016 election to aid him and hurt Hillary Clinton's campaign.
The two Inauguration Day confirmations were fewer than the seven targeted by the Trump transition team. They had hoped to meet the number that President Barack Obama had on his Inauguration Day, but Senate Democrats have objected to many of Trump's nominees.
Though Republicans have a Senate majority and are likely to confirm most if not all of Trump's Cabinet, Democrats can slow down the process by not agreeing to expedite Senate procedure.
The two national security nominees were considered the least controversial of the picks. In order to be confirmed quickly by voice vote, the Senate must be unanimous. Any single senator may object to dispensing with procedural steps, which was why any of the three Democrats could delay Pompeo's nomination.
Senate Minority Leader Chuck Schumer has been negotiating with Majority Leader Mitch McConnell over nominees.
Over the weekend Senate committees announced some movement on confirmation hearings.
The Senate Foreign Relations Committee is scheduled to meet Monday to vote on Rex Tillerson's nomination for secretary of state.
The Judiciary Committee will meet to consider attorney general nominee Sessions on Tuesday, but a vote is expected to be delayed for a week.
Also on Tuesday Trump's choice to head the Health and Human Services Department, Rep. Tom Price, will have a hearing before the Senate Finance Committee. It's his second committee hearing but the Finance panel will be the one to vote on his nomination.
That same day Rep. Mick Mulvaney, Trump's pick for OMB director, will have a hearing before the Senate Budget, Homeland Security and Government Affairs committees. And Linda McMahon, nominated to head the Small Business Administration, will have a hearing before Senate Small Business Committee.
Tuesday will additionally include a Senate Commerce Committee vote on labor secretary nominee Elaine Chao and Wilbur Ross to head the Commerce Department.
Democrats have accused the Republicans of trying to ram through Trump's nominees, complaining that multiple hearings were held concurrently, that required ethics paperwork wasn't delivered in enough time before confirmation hearings and that some of the nominees were too extreme.
McConnell opened debate on the Senate floor Friday by lamenting the situation, especially that Democrats didn't allow Pompeo's confirmation immediately.
"We need to confirm a new director today," McConnell said. "We need to confirm the rest of the Cabinet as quickly as we can."
Schumer has said that his caucus has the right to express objections to nominees. After McConnell spoke on the floor, Sen. Dick Durbin, the No. 2 Senate Democrat, spoke about delays in ethics paperwork and Obama nominees that Senate Republicans held up throughout his tenure.
Oregon Sen. Ron Wyden, an outspoken critic of surveillance, Vermont Sen. Patrick Leahy and Connecticut Sen. Richard Blumenthal were the three Democrats who put out a statement Friday objecting to Pompeo's confirmation Friday.
"No CIA director in history has ever been confirmed on Inauguration Day," their offices said in a joint statement. "The importance of the position of CIA director, especially in these dangerous times, demands that the nomination be thoroughly vetted, questioned and debated."
Trump signed a bill clearing the way for Mattis to be confirmed as his first action as President earlier Friday. Congress passed the waiver -- making an exception to a law requiring defense secretaries be out of the military at least seven years before serving -- earlier this month.