Although his father Harry was a practicing Jew and a member of a Minneapolis synagogue, David Brudnoy was an agnostic who disliked organized religion and was critical of religions that tried to impose their views on others. He did have a bar mitzvah in May 1953, but he was already becoming skeptical of religion and recalled that event as the last time he followed his religious traditions. Years later, he wrote several opinion pieces about his opposition to religious dogmatism. But on the other hand, he also wrote favorably about the good that the church was capable of doing. In one piece, he stated that "...the church itself, for Catholics and non-Catholics alike, is a bulwark of our society. Its severely overburdened clergy are crucial to the development of our youths, to comforting our elders, and to tending our sick."

Over the years, Brudnoy also appeared as a news commentator and host on local TV stations besides WGBH, including WCVB-TV (ABC), WNAC-TV, and WBZ-TV (CBS). He also appeared nationally on the CBS Morning News. He wrote movie reviews for Boston magazine and local community newspapers. During the 1970s he wrote articles for the National Review, and befriended its Editor william F. Buckley Jr. He also wrote for The Alternative (later known as The American Prospect) in the early 1970s, but quit because of the editor's unwillingness to adopt a more liberal position on gay rights. His articles have appeared in The New York Times, The New Republic, and The Saturday Evening Post.

Brudnoy began a career in broadcast commentary in 1971 on Boston's local PBS television station, WGBH-TV. In 1976, he took over as host of his friend Avi Nelson's radio show on WHDH, in the midst of the city's unrest over forced busing and desegregation in schools. He took to the job with ease, and increasingly gained popularity. From 1981 to 1986, he appeared on former Top 40 station WRKO, which was now news and talk, before moving to local stalwart WBZ. The top-rated talk radio host in New England, he appeared in a regular weekday evening slot until his retirement. At the end of his career, Brudnoy was, according to WBZ Radio's promotional materials, derived from Arbitron ratings, among the most-listened-to evening talk hosts in the United States.

Brudnoy was diagnosed with HIV/AIDS in 1988, but kept his treatment a secret until his condition became serious after he contracted pneumonia in 1994. He was absent from public life for some time to fight the disease. Comatose and near death at one point, he eventually returned to reasonable health. It was at that time, in order to conserve his strength, that he broadcast his show from his apartment in the Back Bay section of Boston during part of 1994. Once he was able to return to the air, Brudnoy announced the creation of a fund to fight AIDS. His illness inspired him to publish his autobiography; at the time, it was not a best-seller, but after he died, it became a collector's item, since his publisher had originally let it go out of print and now many of his fans wanted copies of it.

In 1990, his WBZ show was canceled in favor of a less expensive syndicated show hosted by Tom Snyder, but a mass public response, including support from The Boston Globe and the Boston Herald, helped lead to his quick return to the station's lineup.

Brudnoy came out publicly in 1994, after returning from hospitalization to overcome his long-hidden fight with AIDS. Having attracted a largely conservative audience based on his political views, traditional anti-homosexual conservatives rejected him, though others admired him for his courage. Despite the controversy, his ratings reportedly did not suffer as a result. The controversy was rekindled somewhat after the release of his autobiography, in which he described a history of sexual excesses. Brudnoy did not attempt to mask his sexuality during his adult life, but also made no direct indications of it; it was well-known among his colleagues in broadcasting long before he spoke publicly about it. His closest and oldest friend was Psychologist Dr. Ward Cromer, with whom he took dozens of trips abroad, and who was incorrectly assumed by many to be Brudnoy's sexual partner. Neither of them used that phraseology to describe their relationship, preferring a more accurate title of "best friend". When Brudnoy died, it was Cromer who became executor of his estate.

Brudnoy's popularity escalated him into the Boston media elite, and he was the host of numerous social gatherings at his upscale Back Bay apartment, mixing students, media personalities, and politicians. After his bout with AIDS, Brudnoy began broadcasting from his apartment four nights out of five, welcoming his radio guests into his home and eagerly offering them cocktails. When he returned to the air in early January 1995, after his first battle with HIV/AIDS kept him off the air for ten weeks, Boston Mayor Thomas Menino formally declared January 5 as "David Brudnoy Day" due to his popularity.

In 1997, Brudnoy was awarded the Freedom of Speech Award from the National Association of Radio Talk Show Hosts, and was nominated for the major market "Personality of the Year" Marconi Radio Award by the National Association of Broadcasters. In 2001, he celebrated his 25th anniversary on the air. He was inducted to the Massachusetts Broadcasters Hall of Fame, posthumously, in 2008.

In 2000, Brudnoy declared himself a member of the Libertarian Party.

In September 2003, he was diagnosed with Merkel cell carcinoma, a rare form of skin cancer. After hospitalization and treatment, including another period of being considered near death, the cancer went into apparent remission, and Brudnoy returned to work, with a strained voice, in March 2004. However, in November 2004, doctors discovered that cancer had spread into his lungs and kidneys, forcing him to undergo dialysis in addition to cancer treatment.

Brudnoy checked into Massachusetts General Hospital on December 3, 2004. On December 8, Brudnoy made his last radio broadcast on his show via a deathbed interview with WBZ reporter Gary LaPierre. The following day, Brudnoy ordered his doctors to remove all artificial life support systems, leaving him only with oxygen, morphine, and minimal food. He died hours after having the support removed, on December 9, 2004.

A public memorial was held for Brudnoy on February 27, 2005, at the Cutler Majestic Theater in Boston, arranged by his WBZ colleagues and Emerson College (which had previously awarded him an honorary doctorate). The memorial Service included the participation of the brothers of the Phi Alpha Tau fraternity of Emerson College whom Brudnoy had mentored.

After a few days of on-air remembrance, Brudnoy's time slot was assigned to Paul Sullivan, who had previously taken over two hours of Brudnoy's shift when Brudnoy's illness necessitated reducing his show from five hours to three. Sullivan too would die of cancer, on September 9, 2007.