WDBJ-TV first signed on the air on October 3, 1955, owned by the Times-World Corporation, which also published the Roanoke Times and Roanoke World-News. It was the third TV station to launch in Roanoke, joining NBC affiliate WSLS-TV and the short-lived WROV-TV. CBS was the natural network fit, owing to WDBJ radio's long affiliation with the CBS Radio Network. The original transmitter went up on Mill Mountain because the South Carolina station WSPA-TV in Spartanburg was already claiming the desired Poor Mountain frequency. By 1956, after the interference question was settled, WDBJ moved its transmitter to Poor Mountain, where the antenna still operates today. Within three years of sign-on the station had overtaken WSLS to become the ratings leader, and with brief interruptions it has held that position ever since.

For 35 years, reruns of The Andy Griffith Show held the 5:30 p.m. slot. It started in 1984 as a piece of programming and turned into a local institution — a half-hour of Mayberry that consistently beat first-run syndication and competing newscasts. Even when WDBJ's management realized the show was holding back local news ratings, they could not bring themselves to move it. Only after WDBJ acquired sister station WZBJ in 2018 — providing a place to relocate Griffith — did WDBJ finally launch a 5:30 p.m. newscast on April 1, 2019. The station also runs Friday Football Extra during the high school football season and the university-produced Virginia Tech Sports Today during Hokies football and basketball. WDBJ has additional newsrooms in Lynchburg/Bedford, the New River Valley, Danville, and Lexington.

Times-World merged with Norfolk-based Landmark Communications in 1969 — and the WDBJ stations had to be divested, because FCC rules at the time barred the new combined company from owning the Roanoke broadcaster. WDBJ was sold to South Bend, Indiana-based Schurz Communications. The radio sister stations went to separate owners. In 2002, the TV station moved into a new high-definition-ready studio on Hershberger Road. In March 2015, the FCC fined WDBJ $325,000 — at the time the largest fine the agency had ever levied against a TV station for a single instance of indecency — over a roughly three-second portion of an image that had inadvertently aired during a 2012 newscast. Six months later, Schurz announced it was exiting broadcasting; Gray Television completed the $442.5 million acquisition that included WDBJ in February 2016.

Alison Bailey Parker grew up in Martinsville, attended Patrick Henry Community College and James Madison University, interned at WDBJ in 2012, worked for an ABC affiliate in New Bern, North Carolina, and was hired at WDBJ in 2014 as a correspondent for the morning show. Adam Laing Ward was born in Daleville, grew up in Salem, and graduated from Virginia Tech in 2011 with a degree in communications and media studies. He had been at WDBJ as a videographer since July 2011. Both were murdered on the morning of August 26, 2015, during a live broadcast at Bridgewater Plaza in Moneta, by a former WDBJ employee who had been fired in 2013. Vicki Gardner, who was being interviewed, was also shot. She survived. The killer drove from the scene to the Roanoke-Blacksburg Regional Airport, switched cars, headed east on I-81 and I-66, and shot himself during a police pursuit in Fauquier County hours later. The station's newsroom has kept telling Roanoke its stories every morning since. The Adam Ward Scholarship at the Salem Educational Foundation, the Alison Bailey Parker Memorial Scholarship at Patrick Henry Community College, and the Alison B. Parker studio at JMU keep their names where the work continues.