Sanders was also a outfielder for nine seasons in Major League Baseball (MLB) with the New York Yankees, Atlanta Braves, Cincinnati Reds, and San Francisco Giants.

Sanders played college football as a cornerback for the Florida State Seminoles, winning the Jim Thorpe Award in 1988 before being selected by the Falcons fifth overall in the 1989 NFL draft.

In 2020, Sanders was named head coach of the Jackson State Tigers, leading them to two consecutive Celebration Bowl appearances and the school's first undefeated regular season in 2022.

The Kansas City Royals selected Sanders out of North Fort Myers High School in the sixth round of the 1985 Major League Baseball draft.

Sanders started by stepping up to the plate with one out and a runner on third, drawing a dollar sign in the dirt before the pitch and then failed to run to first base after hitting a routine pop fly to shortstop, trotting back to the dugout instead.

On July 31, Sanders hit a key three-run homer to spark a comeback win against the Pittsburgh Pirates during the Braves' run to the National League West Division title.

[23] Before the 1992 season, Sanders reworked his NFL deal, whereby he still reported to the Falcons for training camp in August, but was allowed to rejoin the Braves for the postseason.

[6] In four games of the 1992 World Series, Sanders batted .533 with four runs, eight hits, two doubles, and one RBI while playing with a broken bone in his foot.

The following year, he played in 33 games for the Reds, recording a .240 batting average with 16 stolen bases before being traded to the San Francisco Giants.

[6] After Sanders' release from the Reds, he signed a minor league contract with the Toronto Blue Jays, who assigned him to the Triple-A Syracuse SkyChiefs.

[30] In his final professional baseball game, Sanders hit a solo home run and an RBI single in Syracuse's 12–6 win over the Toledo Mud Hens.

[31] As those in MLB and the NFL urged Sanders to concentrate on only one sport (similar to what they did with Bo Jackson), he often explained, "football is my wife and baseball is my mistress.

Despite fumbling (and recovering) his first NFL punt return (which was re-kicked on a penalty), Sanders ran for a touchdown on his second attempt of his first game.

In Super Bowl XXIX, he recorded an end zone interception in the fourth quarter as the 49ers won over the San Diego Chargers, earning him his first championship ring.

The teams in the "Deion Sweepstakes", as it was called by the media, were the Philadelphia Eagles, Oakland Raiders, Miami Dolphins, New Orleans Saints, San Francisco 49ers and the Dallas Cowboys, who had lost their starting cornerback Kevin Smith to injury for the rest of the season.

He went on to help the Cowboys win their third title in four years in Super Bowl XXX against the Pittsburgh Steelers, where he returned a punt for 11 yards and caught a 47-yard reception on offense, setting up Dallas's first touchdown of the game and a 27–17 victory.

[42] On December 23, 2002, the Redskins waived Sanders from the reserve/retired list in order to potentially allow him to play for the Oakland Raiders in the 2002–03 NFL playoffs.

[43] In 2004, Sanders announced his intention to come out of retirement after being convinced by his friend Joe Zorovich, Baltimore Ravens cornerback Corey Fuller, and linebacker Ray Lewis to play.

Against the Buffalo Bills in Week 7 of 2004, Sanders scored his ninth career interception return touchdown, moving him into a tie with Ken Houston and Aeneas Williams, and behind Rod Woodson (with 12), for second place all-time in the statistical category.

In 2017, he became the offensive coordinator for Trinity Christian High School giving him the opportunity to coach his sons Shilo and Shedeur Sanders, along with his eldest son Deion Jr.[50] On September 21, 2020, Deion Sanders became the 21st head coach of the Jackson State Tigers of the historically black (HBCU) Jackson State University.

In his first season in spring 2021, abbreviated and delayed from its normally intended fall 2020 schedule due to COVID-19 disruptions, he led the Tigers to a 4–3 record, with one win by forfeit.

[72] Sanders did not attend classes or take final exams during the fall semester (1988) of his senior year at Florida State, yet played in the Sugar Bowl against Auburn.

This caused the NFL to institute its own "Deion Sanders rule", whereby a prorated portion of a player's signing bonus counted against the salary cap.

[77] Sanders has also appeared in television commercials for such companies as Nike, Pepsi, Burger King, Pizza Hut and American Express.

In 2008, Sanders and his wife starred in the reality show Deion & Pilar: Prime Time Love, centering on them and their five children living in the small town of Prosper, Texas.

In 2015, he competed against singer Justin Bieber in an episode of Spike's Lip Sync Battle and won with performances of "Play That Funky Music" by Wild Cherry and "Like a Virgin" by Madonna.

[85] The commercial depicted Sanders suggesting he could still play at a level higher than the rookies in the 2013 NFL draft and deciding to make a comeback.

A voiceover then instructs viewers to watch NFL Network for offseason and draft coverage at the end noting in a deadpan voice that "the next rookie sensation probably won't be Leon Sandcastle.

[104] On September 2, 2005, in response to Hurricane Katrina, Sanders challenged all professional athletes in the four major sports to donate $1,000 each to relief efforts, hoping to raise between $1.5 and $3 million.

[110][111] In 1997, Sanders was going through a dark time in his life when his first marriage was ending and said he attempted suicide by driving a car off a cliff in Cincinnati while playing for the Reds.