Whitlock was an all-state offensive lineman at Warren Central High School in Warren Township in the eastern part of Indianapolis, and he blocked for quarterback Jeff George, who later became the first overall pick in the 1990 NFL Draft. He attended Ball State University on a football scholarship, lettering two years as an offensive lineman. He graduated with a degree in journalism in 1990.
Whitlock's first job was working part-time for The Herald-Times in Bloomington, Indiana. His first full-time job was as a reporter for The Charlotte Observer. After approximately one year there, he joined the Ann Arbor News in 1992 and spent two years covering the University of Michigan.
In 1994, Whitlock was hired by the Kansas City Star. The Scripps Howard Foundation awarded Whitlock its National Journalism Award for commentary on March 7, 2008. Whitlock was the first sportswriter to win the award and $10,000 prize. On August 16, 2010, the Kansas City Star announced Whitlock's departure from that paper.
In 2002, Whitlock started writing columns for ESPN.com's Page 2. Whitlock had guest-hosted several ESPN TV shows, including Jim Rome Is Burning, and Pardon the Interruption. He was a regular fill-in host on The Jim Rome Show on Premiere Radio Networks. He also appeared regularly on ESPN's The Sports Reporters Outside the Lines.
In 2006, Whitlock announced the departure of his online column from ESPN.com's Page 2 in favor of AOL Sports, but initially expected to continue his television work for ESPN. However, after the announcement, Whitlock was interviewed by sports blog The Big Lead, and disparaged two of his ESPN colleagues. Whitlock labeled Mike Lupica "an insecure, mean-spirited busybody", and called Robert "Scoop" Jackson a "clown", saying that "the publishing of [Jackson's] fake ghetto posturing is an insult to black intelligence." Jackson, like Whitlock, is African-American. Whitlock then disappeared from all ESPN television work. He soon announced to The Kansas City Star readers in September 2006 that he was fired altogether from ESPN as a result of his remarks; he wrote that the company doesn't tolerate criticism and acted as they saw fit. Whitlock's first AOL Sports column was published September 29, 2006.
Whitlock's first Fox Sports on MSN column was published August 16, 2007. On February 10, 2012, in the middle of the Knicks' 92–85 victory over the Los Angeles Lakers, with Jeremy Lin scoring a career-high 38 points, Whitlock posted on Twitter that "some lucky lady in NYC is gonna feel a couple inches of pain tonight." Silvie Kim wrote in Hyphen that Whitlock "reinforced the insipid and insidious 'small Asian penis' stereotype. The Asian American Journalists Association demanded an apology. Later, Whitlock said, "I debased a feel-good sports moment. For that, I'm truly sorry."
Whitlock originally expected to be an integral part of the launching of the Fox Sports 1 sports television channel in August 2013, but then came to feel that that television work would come at the expense of his writing. Therefore, upon meeting with ESPN President John Skipper, Whitlock decided to leave Fox Sports and accept Skipper's offer to return to ESPN.
Whitlock has also been published in Vibe, Playboy, and The Sporting News. In the June 2008 issue of Playboy, he wrote a 5,000-word column questioning America's incarceration and drug-war policies. Playboy headlined the column "The Black KKK", which provoked Whitlock into writing two columns, one in the Kansas City Star and another on Foxsports.com, criticizing Playboy editorial director Chris Napolitano for the misleading and inflammatory headline.
He was the host of a morning-drive talk show, "Jason Whitlock's Neighborhood" on Sports Radio 810 WHB.
Whitlock was the celebrity spokesman for Big Brothers Big Sisters of Greater Kansas City.
His new website 'The Undefeated.com' was scheduled to launch on ESPN.com sometime in the summer of 2015. After over a year and a half of delays, ESPN announced that Whitlock would no longer serve as the editor in chief for 'The Undefeated', replaced on an interim basis by Leon Carter, the editorial director for the site. In October 2015, Whitlock's employment at ESPN ended.