He played college basketball for the St. John's Red Storm and was selected by the New York Knicks in the first round of the 1987 NBA draft with the 18th overall pick.

He played in the NBA for the Knicks, Los Angeles Clippers, Indiana Pacers, Denver Nuggets, Toronto Raptors, Utah Jazz, and Houston Rockets in a career spanning from 1987 to 2004.

After retiring from playing basketball, Jackson became a broadcast commentator for ESPN and ABC alongside his former coach Jeff Van Gundy and play-by-play man Mike Breen.

[2] While at St. John's, Jackson developed an unusual free-throw line ritual of extending his hand and "cupping" his thumb and index finger around the rim.

After sweeping Charles Barkley's Philadelphia team in the opening round, the Knicks faced the upstart Chicago Bulls, led by Michael Jordan, in the Eastern Conference semifinals.

Near the end of game two, Jackson en route to a fast break layup in the fourth quarter looked back and stuck out his tongue at Jordan before finishing the layup; Jordan responded with a 40+ PPG average the remainder of the series, and led Chicago to a 4–2 series victory.

Consequently, he began to face stiff competition from backup guard Rod Strickland, and then after Strickland was traded away, Maurice Cheeks, to the point where in their decisive first-round game five against Larry Bird, Kevin McHale, Robert Parish, Dennis Johnson and the Boston Celtics at the Boston Garden, Knick coach Stu Jackson decided to bench Mark Jackson for the entire game; New York defeated Boston to advance to the second round, where they lost to the eventual champion Detroit Pistons in five games.

After the 1991–92 season, he was traded to the Los Angeles Clippers, a trade that saw Charles Smith and Doc Rivers go to the Knicks (this was actually a three-team deal, with the Clippers also obtaining Stanley Roberts from the Orlando Magic for draft picks; Roberts had become superfluous in Orlando when the Magic won the draft lottery for his college teammate, Shaquille O'Neal).

Jackson would eventually appear in his only NBA Finals as the Pacers' starting point guard in 2000, when they lost to the Los Angeles Lakers in six games.

Jackson was reported to have caused friction and disputes in the Jazz locker room by attempting to persuade his teammates that he should become the team's starting point guard instead of Stockton.

Jackson played in only 42 games as a Rocket and, experiencing a large drop-off in production, finished his career at the season's end.

In response to his penchant for backing down opposing point guards in the post for 15 or more seconds at a time,[dubious – discuss] the league instituted the five-second back-to-the-basket violation, sometimes called the "Mark Jackson Rule", prohibiting an offensive player from dribbling with his back to the basket for more than five consecutive seconds when below the free throw line.

In the 2012–13 season, with strong performance from Stephen Curry and Klay Thompson, Jackson led the Warriors to a 47–35 record and a #6 seed in the Western Conference playoffs.

The Warriors' front office said the team was better than when Jackson arrived but felt a different coach was needed to win an NBA championship.

A basketball card depicting Jackson has gained notoriety for featuring the Menéndez brothers in the background watching as courtside spectators.

[16] In May 2023, in the days following the announcement of Joel Embiid as the 2022–23 NBA MVP, but before the details of individual votes were known, there was public criticism—most notably by Charles Barkley on TNT's Inside the NBA—of the only voter (at that point still unnamed) who didn't include the Denver Nuggets center Nikola Jokić in his top five.

[17] As the NBA released the individual voting ballots,[18] it was revealed that ESPN's analyst Jackson was the voter in question.

[34] In June 2012, Jackson revealed that he had been the target of an extortion threat based on an extramarital affair and nude photos taken in 2006.

"I recognize the extremely poor judgment that I used both in having an affair six years ago—including the embarrassing communication I exhibited during that time," said Jackson, "and in attempting to deal with the extortion scheme at first by myself.