Drafted by the New York Mets out of Junípero Serra High School in San Mateo, California in the first round of the 1985 amateur draft (#20 overall), Jefferies hit .331 in his first year in the minor leagues, moving from Kingsport of the Appalachian League (rookie) to Jackson of the Texas League (AA) in two years. He was named Minor League Player of the Year for both 1986 and 1987, hitting .367 with 20 home runs, 48 doubles and 101 RBI for Jackson in the latter year, earning Jefferies a brief call-up the New York Mets at the end of the 1987 season. He went 3 for 6 in 6 games, at the age of 19, making him the youngest player in the Major Leagues that season.
The Mets decided they needed to make room for Jefferies, but didn't know where to play him, as the veteran team was full at the spots Jefferies played in the minor leagues (shortstop, third base and second base). The outfield was full also, with the team finding it difficult to get outfielders Lenny Dykstra and Mookie Wilson playing time alongside Darryl Strawberry and Kevin McReynolds, so Jefferies was sent to AAA Tidewater to start the 1988 season.
After spending most of the 1988 season at AAA (where he hit .282), Jefferies was recalled at the end of August and allowed to play out the year as a starter, mostly at third base. He responded by hitting .321 over the last 29 games of the 1988 season as the team finished with a 100-60 record to win the National League East.
The Mets made a full-time roster spot for Jefferies when they traded Wally Backman to the Minnesota Twins, leaving second base open for Jefferies. But Jefferies faltered, hitting .258 with little selectivity as a rookie in 1989.
During a game against the Philadelphia Phillies on September 27, 1989, Jefferies was the last batter to ground out before the Mets lost the game. Jefferies then heard some unkind comments from his former teammate, Roger McDowell and then charged the mound starting a bench-clearing brawl.
In response to criticism from teammates, on May 24, 1991, Jefferies pleaded his case in an open letter read on WFAN, New York's sports radio station. In the letter, Jefferies wrote: "When a pitcher is having trouble getting players out, when a hitter is having trouble hitting, or when a player makes an error, I try to support them in whatever way I can. I don't run to the media to belittle them or to draw more attention to their difficult times. I can only hope that one day those teammates who have found it convenient to criticize me will realize that we are all in this together. If only we can concentrate more on the games than complaining and bickering and pointing fingers, we would all be better off."
In 1990, Jefferies raised his batting average up to .283 while scoring 96 runs and hitting 40 doubles, but the team finished 2nd for the second straight year. He slipped in 1991, hitting .272 with 30 extra base hits in 486 at bats as the team slipped to 5th place. That offseason the team traded him, along with McReynolds and infielder Keith Miller, to the Kansas City Royals for former All-Star pitcher Bret Saberhagen and utility man Bill Pecota, ending his stay with the Mets.
After playing the 1992 season with the Royals, he moved on to the St. Louis Cardinals, where he would have his two best seasons, batting .342 and .325, respectively, while finding a home at first base and being named to the National League All-Star team in both the 1993 and 1994 seasons. He signed a lucrative contract with the Philadelphia Phillies after the 1994 season due to a dispute over a no-trade clause the Cardinals wouldn't give him, and he moved to the outfield for the Phillies, where he performed adequately over the 1995, 1996 and 1997 seasons, but injuries to his thumb and hamstring hampered his effectiveness. In 1998, he was traded mid-season to the Anaheim Angels, where he hit .347 in 19 games before moving to the Detroit Tigers the next year. He hit a collective .231 for the Tigers over two seasons before he retired in 2000.
For his career, Jefferies had a career .289 batting average with 126 home runs, 663 RBIs and 196 stolen bases.
Jefferies resided in Pleasanton, California with his wife Jeannie Marshall and kids. He was a hitting instructor at Total Players Center in Pleasanton, California before opening his own Gregg Jefferies Sports Academy also in Pleasanton, California. He coached Troy Channing, who was selected in the MLB Draft.
Jefferies now resides in Yorba Linda, California and is a hitting instructor at Hard-9 training facility in Anaheim, Ca.