Three Republicans crossed the aisle to seal her appointment by a vote of 53 to 47.
Justice Jackson's appointment fulfils President Joe Biden's campaign promise to put a black woman on the court.
Chuck Schumer, the majority leader, called it a "joyous day" for the US.
The vote was overseen by Vice-President Kamala Harris, the first black woman to hold the office.
Ms Jackson, 51, will replace Justice Stephen Breyer, a fellow liberal judge for whom she once clerked, upon his retirement in June.
The lifetime appointment will likely see Ms Jackson on the bench for decades, but will not shift the ideological balance of the current court, with its 6-3 conservative majority.
Ms Jackson has said she has a "methodology" to deciding cases but not an overarching philosophy. And she agreed with Republican senators about the importance of abiding by the text of the Constitution, as it was intended by the founders.
During her confirmation, Democrats touted her experience working as a public defender. She will be the first Supreme Court justice since Thurgood Marshall - the first black Supreme Court justice - to have career experience representing criminal defendants.
The jurist, a Washington DC native, currently sits on the influential US court of Appeals for the DC circuit. She has two degrees from Harvard University and once served as editor of the Harvard Law Review. She worked as a public defender in Washington before joining a private practice prior to her judicial appointments.
Some Republicans took issue with clients Ms Jackson took on as a public defence lawyer - namely terrorism suspects held at Guantanamo Bay, with some accusing her of being soft on crime.
Others, however, applauded the diversity of experience her legal career would bring to the bench over the course of what was at times highly fractious and almost entirely polarised six week confirmation process.
Senator Lisa Murkowski of Alaska, one of three Republicans to vote in favour of Justice Jackson said this decision rested, in part, as a "rejection of the corrosive politicisation" that has come to shape the confirmation process.
The new justice "will bring to the Supreme Court a range of experience from the courtroom that few can match given her background in litigation," Ms Murkowski said.
The top court plays a crucial role in American public life and is often the last word on highly contentious laws and disputes between states and the federal government.
Photo CNBC Caption: US Senate confirms Justice Ketanji Brown Jackson