Bayless was born in Oklahoma City, Oklahoma. The first child of John and Levita Bayless, he was named John Edward Bayless II on his birth certificate, but his father immediately began calling him Skip or Skipper. The name stuck, and Skip Bayless was never called John by his parents. He eventually had his name legally changed to Skip. His brother is the chef, restaurant owner and TV personality Rick Bayless

Bayless graduated from Northwest Classen High School and Vanderbilt University.

Bayless went directly from Vanderbilt to The Miami Herald, where he wrote sports features for two years before being hired away by the Los Angeles Times. There, he was best known for investigative stories on the Dodgers' clubhouse resentment of "golden boy" Steve Garvey and his celebrity wife Cyndy and on Rams owner Carroll Rosenbloom's behind-the-scenes decisions to start different quarterbacks each week (James Harris, Pat Haden or Ron Jaworski). Bayless also won the Eclipse Award for his coverage of Seattle Slew's Triple Crown.

At 25, Bayless was hired by The Dallas Morning News to write its lead sports column, and two years later, the rival Dallas Times Herald hired him away by making him one of the country's highest paid sports columnists—prompting The Wall Street Journal to do a story on the development. Bayless was voted Texas sportswriter of the year three times.

In 1989, Bayless wrote God's Coach, about the rise and fall of Tom Landry's Dallas Cowboys. Following the Cowboys' Super Bowl victory in 1993, Bayless wrote The Boys, which broke the story that coach Jimmy Johnson and owner Jerry Jones were not "best friends" and correctly predicted that Jones would fire Johnson no matter how much success the team had. (Jones fired Johnson after the Cowboys won another Super Bowl the following year.)

Following a third Cowboys Super Bowl win in four seasons, Bayless wrote the third and final book of his Cowboys trilogy, Hell-Bent: The Crazy Truth About the "Win or Else" Dallas Cowboys.

After covering the Cowboys through the 1996 season, Bayless chose to leave Dallas after 17 years and become the lead sports columnist for the Chicago Tribune. In his first year in Chicago, Bayless won the Lisagor Award for excellence in sports column writing and was voted Illinois sportswriter of the year.

Bayless eventually had a highly publicized dispute with the Tribune's executive editor, Ann Marie Lipinski, over limiting all Tribune columns to just 650 or so words. Bayless quit over the policy and was immediately hired by Knight Ridder Corporation to write for its flagship newspaper, the San Jose Mercury News. While in San Jose, Bayless became a fixture on ESPN's Rome is Burning and in a weekly Sunday Morning SportsCenter debate with Stephen A. Smith, "Old School/Nu Skool." ESPN hired Bayless full-time in 2004 to team with Woody Paige on ESPN2's Cold Pizza and to write columns for ESPN.com. In 2007, Bayless stopped writing columns to concentrate on what is now called ESPN First Take (formerly Cold Pizza) and on ESPN's afternoon show, First and 10, as well as increased presence on ESPN's 6 p.m. SportsCenter with segments such as "The Budweiser Hotseat".

Skip Bayless has occasionally substituted as host for syndicated radio program The Jim Rome Show. He has also previously contributed to ESPN as a recurring panelist on The Sports Reporters, NFL Prime Monday (now ESPN Monday Night Countdown) in the 1990s, and Jim Rome is Burning. For three years (1998—2001), Bayless was a contributor at major championships for the Golf Channel.

KTCK Sports Radio 1310 "The Ticket"

In 1994 Bayless left his show at KLIF in Dallas to help start the city's first sports talk radio station, KTCK Sports Radio 1310, "The Ticket." For two years Bayless was the primary host on the 6-9 a.m. morning show as "the Ticket" became one of the country's most successful sports stations. Bayless also was an original investor and when the ownership decided to accept a lucrative offer to sell the station, the new owners bought out Bayless' contract. He immediately became a regular on ESPN Radio's first national show, The Fabulous Sports Babe, and later co-hosted a weekend show on ESPN Radio with Larry Beil. He was also a regular on Chet Coppock's show on Sporting News Radio. For three years he was the primary guest host on The Jim Rome Show.

Cold Pizza/ESPN First Take

Bayless is featured in debate segments on what is now known as ESPN First Take(nee Cold Pizza) and the segments are re-aired as First and 10 in the afternoons. Bayless debates the day's 10 hottest sports topics with a rotation of sportswriters and ex-athletes including Stephen A. Smith, Greg Anthony, Jalen Rose, Marcellus Wiley, Shaun King and 2 Live Stews (Ryan and Doug Stewart). Donovan McNabb, rappers Lil Wayne, Bow Wow, Wale and Donnie Wahlberg have also taken on Bayless. He has also taken on Chad Ochocinco twice, once during the preseason in the Cincinnati Bengals locker room and the second took place in Bristol on October 29, 2009 during the Bengals bye week.