The vote count was 54-45.
Mullin, a businessman and former mixed-martial arts fighter, backs Trump's hardline immigration view but signalled during a confirmation hearing that he would dial back some aggressive immigration policies, including a directive that said federal immigration officers could forcibly enter private homes or businesses without judicial warrants.
Democrats have blocked funding for the 260,000-person Department of Homeland Security since mid-February in a push to scale back Trump's immigration enforcement tactics. Airport security screeners who have missed pay cheques have increasingly been calling out sick, leading to longer lines in US airports.
Senate Republicans repeatedly have rejected a Democratic bill that would have paid Transportation Security Administration workers while negotiations on immigration enforcement practices continued.
The Trump administration began deploying federal immigration officers at airports on Monday to help with screening but the impact remained unclear.
The new leadership at DHS offers the Trump administration a chance to pivot away from Noem, a former governor of South Dakota who put herself at the forefront of Trump's mass deportation effort.
Both Republican and Democratic lawmakers sharply criticised Noem at congressional hearings in early March over her remarks painting two US citizens fatally shot by federal immigration officers in Minneapolis as perpetrators of "domestic terrorism" even as video evidence undercut those claims.
Noem also faced scrutiny at the hearings over a $US220 million ad campaign that was awarded to Republican-connected firms without a standard contract bidding process.
Trump fired Noem after the hearings, saying she would depart by March 31 and become special envoy to a new Shield of the Americas initiative to promote his security policies in the Western Hemisphere.
During a Senate confirmation hearing, US Senator Rand Paul, the top Republican on the panel, slammed Mullin for a history of violent rhetoric, including remarks in February condoning an attack on Paul in 2017 that left him with broken ribs and a damaged lung.
While Paul opposed Mullin's nomination, Democratic Senator John Fetterman, a moderate from Pennsylvania, provided backing that permitted Mullin to advance to a Senate vote.
Public backing for Trump's immigration policies diminished in recent months as masked federal agents surged to US cities to search for possible immigration offenders.
