Williams was raised in a middle class Irish Catholic home. In his childhood his family moved from his birth place, Ridgewood, New Jersey, to Elmira, New York. He lived in Elmira for ten years, before moving to Middletown, New Jersey.

He graduated from Mater Dei High School, a Roman Catholic high school in the New Monmouth section of Middletown. While in high school, he was a volunteer firefighter for three years at the Middletown Township (New Jersey) Fire Department. His first job was as a busboy at Perkins Pancake House.

After high school, he attended Brookdale Community College, before transferring to George Washington University, and then to The Catholic University of America. He did not graduate, instead taking an internship with the administration of President Jimmy Carter. He now calls leaving college one of his "great regrets."

After working in the lobbying arm of the National Association of Broadcasters, Williams began his broadcasting career at KOAM-TV in Pittsburg, Kansas in 1981. A year later he moved back to Washington, D.C. and worked at WTTG-TV as general assignment reporter. Williams joined NBC News from WCBS in New York in 1993 and became the network's chief White House correspondent in 1994. In 1996, Williams began anchoring The News with Brian Williams on MSNBC and rebroadcast on CNBC.

Williams became anchor of NBC Nightly News on December 2, 2004, and his first year in that post was marked by coverage of two disasters: the Asian tsunami and Hurricane Katrina. NBC personnel felt that the program became his program (rather than Tom Brokaw's) with his coverage of the tsunami, and his reporting on Katrina, including from inside the New Orleans Superdome, was singled out for praise by industry observers. His work helped earn NBC a Peabody Award, the Peabody committee concluding that Williams and the Nightly News staff "exemplified the highest levels of journalistic excellence in reporting on Hurricane Katrina."

Nightly News was the ratings leader among the network evening news programs when Williams became anchor, and it maintained that position until falling slightly behind ABC's World News in the first half of 2007. Nightly News regained the lead later in the year and expanded it beginning in the fall of 2008. By 2010, Williams was viewed as the country's leading news anchor and drawing comparisons to Walter Cronkite.

When Williams succeeded Tom Brokaw as anchor of NBC Nightly News, his annual salary was reported to be $8 million, and by October 2006, it had reportedly increased to $10 million.

Williams frequently appears on The Daily Show as a celebrity guest interviewed by Jon Stewart. He appeared on the Weekend Update segment of Saturday Night Live before hosting the program on November 3, 2007. He has also appeared as a fictionalized version of himself on NBC's 30 Rock.

Brian also regularly appears on Late Night with Jimmy Fallon, where he slow jams the news of the previous week as Fallon sings and reiterates what Brian says.