At age 39, Buttigieg also represents another "first" as a millennial and the youngest person nominated to Biden's Cabinet.
Arizona Sen. Kyrsten Sinema, the country's first openly bisexual senator, was presiding over the Senate Tuesday and announced the 86-13 final vote.
He will assume a department with 55,000 employees and a budget of tens of billions of dollars.
Buttigieg tweeted shortly after the confirmation vote that he's "honored and humbled" and "ready to get to work."
In a speech from Wilmington, Delaware, Buttigieg reflected on what the moment means for all LGBTQ Americans when Biden announced his nomination late last year.
"I can remember watching the news -- 17-years-old in Indiana, seeing a story about an appointee of President Clinton named to be an ambassador attacked and denied a vote in the Senate because he was gay -- ultimately able to serve only by a recess appointment," he said. "And I learned something about some of the limits that exist in this country when it comes to who is allowed to belong. But just as important, I saw how those limits could be challenged."
Buttigieg was referring to the nomination of James Hormel to be ambassador to Luxembourg under then-President Bill Clinton in 1998. Senate Republicans held up the nomination in protest for two years until Clinton made the appointment himself, without confirmation, while the Senate was in recess. He connected the memory to his own confirmation hearing last month in an interview with ABC's "The View."
"As I was in that hearing taking those questions from senators, you could see my husband, Chasten, over my shoulder, and that is something that has never happened before for a Cabinet nominee," Buttigieg said. "My hope is that, in turn, makes it easier for the next person to come along, so that this is never even viewed as a barrier by a future generation."
During his hearing, some Republican senators pressed Buttigieg on the cost of Biden's infrastructure plan, which redirects money for green initiatives, before he cleared the Senate Commerce Committee with a 21-3 vote last month.
Following his quick ascent during the 2020 primary, the rising star in the Democratic Party was the only formal rival Biden picked to join his administration after he announced Vice President Kamala Harris as his running mate in August.
Biden spoke highly of Buttigieg following the former mayor's endorsement, saying he reminded Biden of his late son, Beau.
"I don't think I've ever done this before, but he reminds me of my son Beau. And I know to -- that may not mean much to most people, but to me, it's the highest compliment I can give any man or woman," Biden said of Buttigieg last March.
Though Buttigieg would push forward Biden's transportation initiatives, including an ambitious infrastructure plan, the former mayor released his own $1 trillion infrastructure plan last year that included improvements to a range of the country's transportation infrastructure. Its detailed plans to give more power to local communities, called for upgrades to roads and public transportation and also highlighted road safety with a national Vision Zero goal.
LGBTQ rights organizations have praised Buttigieg's nomination as a major step in ensuring the incoming administration reflects the country's diversity.
Sarah Kate Ellis, president and CEO of GLAAD, the world's largest LGBTQ media advocacy organization, congratulated Buttigieg on his historic ascent on social media Tuesday as it became clear the Senate would confirm him.
"His historic confirmation hearing, where he introduced his husband Chasten, was also a milestone for LGBTQ acceptance and representation," she said. "Secretary Buttigieg's vision will improve all Americans' lives and navigate toward needed change to serve communities on the margins. We know he will continue to lead our country's drive for LGBTQ acceptance."
The former mayor came out publicly in 2015 through an essay in the South Bend Tribune while seeking reelection. He was elected with 80% of the vote, more than he received during his previous election. He served in the role from 2012 to 2018.
Other presidential administrations have featured high-ranking LGBTQ officials. Eric Fanning served as Secretary of the Army during the Obama Administration, the first openly gay individual to hold an armed service's top civilian position. In the Trump administration, Richard Grenell served as acting director of National Intelligence, the first openly gay individual to serve in a Cabinet-level position in an acting capacity, but his position was not Senate-confirmed.
Biden's Cabinet also includes the first female treasury secretary, first female director of National Intelligence and first Black defense secretary.
Buttigieg is the fifth Cabinet level official of Biden's to be confirmed by the Senate.
ABC News' Molly Nagle, Justin Gomez, Sarah Kolinovsky and Allison Pecorin contributed to this report.