Brinkley was born in Wilmington, North Carolina, where he began writing for a local newspaper, the Wilmington Morning Star, while still attending New Hanover High School. He attended the University of North Carolina at Chapel Hill, Emory University, and Vanderbilt University, before entering service in the United States Army. Following his 1943 discharge, he moved to Washington, D.C., looking for a radio job at CBS News. Instead, he took a job at NBC News and became its first White House correspondent.

The year 1952 had seen the birth of an electronic-journalism star when Walter Cronkite anchored CBS's coverage of the political conventions. In 1956, NBC News executives were looking for their own breakout newsbiz star. In NBC's efforts to determine which one of Brinkley and Huntley would make the better anchor for NBC's political-convention coverage, an impasse arose: half of the NBC news executives wanted Chet Huntley as solo anchor; the other half wanted Brinkley. Then came the suggestion to have two anchors instead of one. That insight led to Brinkley's pairing with Huntley to cover the Democratic and Republican national conventions.

The match worked so well that the two took over NBC's flagship nightly newscast, with Huntley in New York and Brinkley in Washington, D.C., for the newly christened Huntley-Brinkley Report. Brinkley's dry wit offset the serious tone set by Huntley; and the program proved popular with audiences turned off by the incessantly serious tone of CBS's news broadcasts of that era. The Huntley-Brinkley Report was America's most popular television newscast until it was overtaken, at the end of the 1960s, by the CBS Evening News, anchored by Walter Cronkite.

When Huntley retired from the anchor chair in 1970, the show was renamed NBC Nightly News, and Brinkley co-anchored the broadcast with John Chancellorand Frank McGee. In 1971, Brinkley became the program's commentator, returning for another co-anchor experiment from 1976 to 1979. However, the show was never again as popular as it had been with Huntley. For its part, NBC attempted to launch newsmagazine shows during the 1970s with Brinkley as anchor. None of them succeeded. An unhappy Brinkley left NBC in 1981.

Almost immediately after leaving NBC, Brinkley was offered a job at ABC, where he began hosting a Sunday-morning talk show, This Week with David Brinkley, which featured several correspondents and interviews with a guest newsmaker, followed by an opinionated roundtable of discussion. The format proved highly successful and was soon imitated.

Brinkley stepped down from This Week on November 10, 1996. He had been an electronic journalist for over fifty years and had been anchor or host of a daily or weekly national television program for just over forty years, longer than anyone else.

The full title of Brinkley's 1995 autobiography sums up what he had seen during his legendary broadcasting career: David Brinkley: 11 Presidents, 4 Wars, 22 Political Conventions, 1 Moon Landing, 3 Assassinations, 2,000 Weeks of News and Other Stuff on Television and 18 Years of Growing Up in North Carolina (ISBN 0345374029).

During his career, he won ten Emmy Awards and three George Foster Peabody Awards. In 1992, President George H. W. Bush awarded him the Presidential Medal of Freedom, the nation's highest civilian honor. Bush called him "the elder statesman of broadcast journalism"; but Brinkley was much more humble. In an interview in 1992, he said "Most of my life, I've simply been a reporter covering things, and writing and talking about it".

Brinkley died at the age of 82 at his home in Houston, Texas, from complications after a fall. His body is interred at Oakdale Cemetery, Wilmington, North Carolina.