Together with Chris Russo, he launched Mike and the Mad Dog in 1989 on WFAN in New York City, which ran until 2008 and is one of the most successful sports-talk radio programs in American history.

On April 27, 2018, WFAN announced that Francesa would return to the station for a 3+1⁄2-hour afternoon show, a shorter shift than his original slot.

[6] At CBS Sports, he was initially a behind-the-scenes, statistics-wielding editorial assistant, but network executives were so impressed by his knowledge that he was made a studio analyst for college basketball and football[7] and acquired such a reputation that The New Yorker termed him "Brent Musburger's brain.

In 1989, WFAN was looking for hosts to replace the controversial Pete Franklin in the afternoon drive time period between 3 and 7 p.m. Station management decided to team the knowledgeable, but somewhat dry Francesa with the young and vibrant Chris Russo.

Francesa regularly contributed to the Imus in the Morning program with his views on sports while it aired on WFAN and Westwood One.

On August 14, 2008, it was announced that Russo had decided to leave WFAN, and thus ended the Mike and the Mad Dog show two weeks shy of its 19th anniversary.

On September 10, 2012, Francesa fell asleep live on air during a segment with Yankees beat reporter Sweeny Murti.

He changed his trademark intro to the show to "From the studios of WFAN in New York and simulcast across the country on Fox Sports 1, this is Mike's On: Francesa on the FAN."

During his entire solo run, Francesa hosted the top-rated drive-time sports-talk show in the New York market.

[17] On March 30, 2016, Francesa and Russo hosted a Mike and the Mad Dog reunion show at Radio City Music Hall.

The station confirmed the decision, stating that he would return to afternoon drive, albeit with a shorter show running from 3:00–6:30 p.m. Monday through Friday.

Francesa said that the incident contrasted with the "great character" of the draft class that the Giants claimed to have picked, despite evidence that the shooting was completely random.

[34] After some media members picked up on the comments, such as Francesa's fellow WFAN hosts Boomer and Gio, Francesa retreated from the opinion on his next day's show, but launched a fiery rant on their morning show the same day, accusing them of purposely distributing misinformation about him and his comments.

[37][38] On September 3, 2019, it was announced that WFAN's owner Entercom had acquired the intellectual property of the Mike's On app, and that its content would be integrated into the company's Radio.com platform, with no additional subscription required.

[40][41] Francesa later denied that the incident had occurred, saying on his afternoon show the same day that it was "fake news" and that the media was desperate for a headline.

In response to his first-ever ratings-book loss, Francesa criticized Kay and his cohosts, claiming that "celebrating [their] success now would be the same as spiking the football after finally scoring a TD in a game that is 77–0!

"[44] During his radio comeback, Francesa's show was the target of criticism for reasons ranging from his frequent inaccurate predictions to his treatment of callers.

[45][46] Video clips of Francesa making inaccurate predictions often went viral on Twitter, with players such as Virginia basketball's Ty Jerome coming onto the show to specifically address them.

[52] Francesa's departure left WFAN needing a replacement for its afternoon-drive slot, which was eventually filled by Joe Benigno and Evan Roberts, who had formerly hosted the midday show.

On the first day of his new show, Francesa announced that his political coverage would be "played down the middle," claiming to provide an unbiased centrist perspective.

[57] On March 24, 2020, Francesa returned to daytime sports radio at WFAN for the first time after his second retirement, taking a temporary weekend gig from 9:00 a.m. to 1:00 p.m. on Sundays.

In May 2020, WFAN announced a revamp to its afternoon plans, scheduling Francesa for his first weekday show on the network since his second retirement with a 6:00–7:00 p.m. time window.

[68] Despite having voted for Trump, Francesa claimed in January 2020 that he would provide an "unbiased" moderate political perspective on his Radio.com show.

Francesa underwent emergency knee surgery on August 31, 2006, to repair a shattered kneecap suffered during a golf game the previous day.

[73] In 2022, in partnership with Lee Einsidler's LRE Racing, his horse Casa Creed won the Grade I Fourstardave Handicap at Saratoga.

[80][81] New York Post columnist Phil Mushnick and Francesa have waged a long-running public battle, which has continued into 2022.

He once accused Francesa and Chris Russo of being recorded demanding loyalty oaths from Jews after the September 11 attacks.

Mushnick's counterpart at the New York Daily News, Bob Raissman, sounded similar themes in 2017 - but noted that Francesa's polarizing approach was what got so many listeners to tune in.