Rex Tillerson, the former chief executive of Exxon Mobil, has been sworn in as Trump's Secretary of State after Senate gave approval.
Senators voted 56-43 to approve the 64-year-old Texan.
Democrats mounted a vocal yet unsuccessful campaign to derail the bid.
They said they feared his four-decade career at the energy giant meant he would view the world only through the lens of a corporate executive.
They also questioned whether he would confront Donald Trump when he believes the president is wrong.
But Republicans rejected the complaints and declared Tillerson highly qualified for the job.
As Secretary of State Mr Tillerson will have to deal with matters such as any fallout stemming from Trump's executive order on immigration and travel that bans citizens from seven Muslim-majority countries for 90 days.
Chairman of the Foreign Relations Committee, Senator Bob Corker said Tillerson's experience leading a global enterprise which included forging "deep relations" with world leaders makes him qualified for the role.
One of those world leaders with whom Tillerson has deep relations is Russian President Vladimir Putin.
Opponents on Capitol Hill said the relationship meant Mr Tillerson was too cosy with the leader and would not push back aggressively enough when Moscow acted against US interests.
Tillerson received an honorific Order of Friendship from Putin's government in 2013.
Democrats pressed their case against Tillerson right up until the vote.
Senator Ben Cardin of Maryland, the top Democrat on the Foreign Relations Committee, said Tillerson is unlikely to steer Trump away from pursuing an "unstable, reckless foreign policy."
Cardin said Tillerson's "timid equivocation on American values" throughout his confirmation process led him to predict Tillerson will be a "yes man" to Trump, unable to prevent "the risky, chaotic whims of a demagogue president who is leading us on a march of folly".