Russo joined WFAN in December 1988 as an overnight, weekend, and fill-in host. Former WFAN Morning Show Host Don Imus brought Russo on board the Imus in the Morning show as the sports reporter. Imus also later helped promote Russo’s nickname. By early 1989, his work on Imus led to Russo getting his own regular weekend show on Saturday Mornings. When Pete Franklin’s drive time Show from 3 pm to 7 pm was not renewed by WFAN station management, WFAN paired up Russo with Mike Francesa, who at the time was a co-host on the mid-morning show. The show was dubbed Mike and the Mad Dog and officially launched on September 5, 1989, at 3 PM Eastern Time.

Russo is the only child of Anthony Michael “Tony” (1931–2013) and Vera “Molly” Russo, from Flushing, Queens and England, respectively. Russo married Jeanne Lavelle on May 6, 1995, and they have four children, Timmy, Kiera, Colin, and Patrick. He resides in New Canaan, Connecticut. He is a lifelong, avid San Francisco Giants fan.

On August 14, 2008, Russo reached a mutual agreement with WFAN to release him out of the remainder of his contract. Russo insisted it was solely a personal decision and said, “This has nothing to do with Mike and I hating each other… This is about doing something different. I’m 48 years old and there are not going to be too many more opportunities to break away. It’s time to try something else, but it was a tough decision to make.” On August 15, 2008, Russo phoned Francesa on the show to say an emotional goodbye.

On August 19, 2008, Russo signed a five-year contract with Sirius XM Radio to headline a new sports talk channel called Mad Dog Radio on both Sirius and XM satellite radio. Russo hosts the channel’s anchor program, Mad Dog Unleashed, live from Sirius’s New York studios every weekday afternoon. Russo brought aboard long-time WINS anchor Steve Torre as the new program director of “Mad Dog Radio” and hired Bill Zimmerman (known on the air as “Billy Z”) as the executive producer of his show. The show began airing daily on Sirius Channel 123 and XM Channel 144 on September 15, 2008. The show now airs on Sirius and XM Channel 82.

On October 16, 2009, Russo joined Francesa for a one-hour reunion show at Yankee Stadium, where both were scheduled to broadcast in adjacent booths. Francesa joined Russo on his Sirius XM show later in the day.

On July 9, 2009, Russo reacted to his station being ranked outside the Top 100 stations on satellite radio by berating his entire staff, which included bringing on nighttime host Andy Gresh for an in-person dress-down. Russo concluded by firing his program director, Steve Torre. Torre was later re-hired and it is unknown if the incident was legitimate or a radio skit. On August 28, 2013, Russo announced that he had been signed by Sirius XM for three more years, commencing in September 2013.

Russo’s Sirius XM deal also included daily hosting of a MLB Network TV show, High Heat, which began on March 31, 2014 (and was simulcasted on MLB Network Radio). He signed a new three-year contract, in September 2016. Russo renewed his contract for four more years, in April 2019.

On March 30, 2016, Russo joined Francesa for a Mike and the Mad Dog reunion at Radio City Music Hall.