Tirico joined ESPN in 1991 as a SportsCenter anchor, after four years as Sports Director at CBS affiliate WTVH-TV in Syracuse, New York, during his undergraduate years at Syracuse University. Tirico is noted for his versatile nature and the variety of assignments he has handled for SportsCenter; Tirico has handled the play-by-play for ESPN's Thursday night college football package (1997 to 2005), college basketball coverage (1997 to 2002), NBA coverage (2002 to present), and PGA golf coverage for ABC (1996 to 2006). Tirico has also hosted studio coverage of various ESPN and ABC covered events, including a stint on ESPN's Monday Night Countdown (previously known as NFL Prime Monday) from 1993 to 2001 and ABC's NBA studio shows. He also broadcasts NBA games on ESPN/ABC, and usually does the NBA Finals coverage for ESPN Radio. He anchored the 2009 U.S. Open (tennis) and co-anchored the 2014 World Cup.

Tirico has been paired in the college football booth with Tim Brant, Terry Bowden, Mike Gottfried, Kirk Herbstreit, Lee Corso, and David Norrie. His partners in NBA coverage have included Tom Tolbert, Hubie Brown, and Greg Anthony, and he has worked with Curtis Strange, Judy Rankin, Nick Faldo, and Paul Azinger in PGA coverage. He has worked with Len Elmore on college basketball coverage. Tirico is also partners with Jon Gruden on Monday Night Football.

On April 21 and 22, 2007, he appeared as a guest host, filling in for Michael Wilbon, alongside Tony Kornheiser on ESPN's Pardon the Interruption.

Tirico hosted his first show from WAER radio in Syracuse, N.Y., the station where he started his sports broadcasting career, on the campus of Syracuse University. Fellow Orange alum Bob Costas was his first guest. On September 20, 2007, Tirico began hosting the short-lived Mike Tirico Show on ESPN Radio from 1:00–3:00 pm weekdays (Eastern time). The show filled the empty seat left by Dan Patrick. During the spring of 2008, the title of The Mike Tirico Show, which featured Scott Van Pelt as a co-host, was changed to Tirico and Van Pelt. On May 19, 2009, Tirico announced he would be leaving the show to focus more on his television play-by-play duties, and the name of the show became The Scott Van Pelt Show.

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