Lawmakers greenlighted Senator Sessions as the 84th US attorney general on a mostly party line vote of 52 to 47, with just one Democrat -- Joe Manchin of West Virginia -- joining the Republican majority.
Sessions voted present, and when the tally was announced many senators broke into extended applause for their colleague.
Trump has harangued Democrats for slow-walking his nominees, blasting their unprecedented obstruction as a "disgrace."
He appeared particularly angered by the delay on Sessions, who as attorney general would wield enormous power regarding the administration of justice, including on the issue of voting rights.
Sessions, widely seen as an inspiration for Trump's anti-immigration policies, is just the sixth of 15 cabinet members to be confirmed, in addition to the cabinet-rank positions of CIA director and US ambassador to the United Nations.
A day earlier senators broke into fiercely personal debate, which saw the Democrat Elizabeth Warren barred from speaking after she was deemed to have broken chamber rules on decorum.
Sessions takes charge of the Justice Department and its 113,000 employees, including the 93 US attorneys throughout the country.
He steps in amid a swirling legal debate over Trump's most controversial White House action to date, an executive order temporarily blocking all refugee arrivals and immigration from seven mainly Muslim countries.
The genteel Sessions, who like the president is 70, was an early loyal Trump supporter who became a pivotal figure in his campaign and transition team.
He was a US attorney for the southern district of Alabama from 1981 to 1993, before serving two years as the state's attorney general. He won a seat in the US Senate in 1996.
But in 1986 his career was almost derailed when a US Senate panel rejected his nomination for a judgeship amid concerns over past comments he made about blacks, and over remarks that appeared sympathetic to the Ku Klux Klan.
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