He spent three years playing in the Cubs farm system before making his major league debut May 2, 1988.

Grace signed with the Arizona Diamondbacks on December 8, 2000, with a $6 million, two-year contract after the Cubs declined to offer salary arbitration.

He received $5.3 million in his last season with the Cubs but accepted less money for the opportunity to live year-round at his home in suburban Scottsdale, Arizona with his family.

"[7] Grace wore his familiar number 17 in Arizona where he played for three more seasons, including helping the Diamondbacks win the 2001 World Series.

His .515 career batting average in League Championship Series play is a record for players in at least ten games.

[citation needed] During a 19–1 defeat by the Los Angeles Dodgers in September 2002, Grace pitched one inning of relief.

Grace also impersonated teammate Mike Fetters, who from the stretch would take a deep breath and then quickly turned his head towards the catcher.

Grace spent 2014 as hitting coach for the Diamondbacks' Class A Short Season affiliate Hillsboro Hops of the Northwest League.

[15] After his retirement as a player, Grace continued his involvement in the game as a television color commentator for the Diamondbacks and for Fox Saturday Baseball.

[16] In February 2017, Grace was named as a baseball analyst for Diamondbacks games by Fox Sports Arizona.

[17][18] In February 2020, Grace was hired as an analyst for select Chicago Cubs games on Marquee Sports Network.

[20] On August 3, 2006, Grace led the Wrigley Field crowd in singing "Take Me Out to the Ball Game" during the seventh-inning stretch of the second game of a doubleheader between the Cubs and Diamondbacks; his appearance helped to improve his relationship with the Cubs, which had been strained since he left the team after the 2000 season.

[21] Grace became eligible for the National Baseball Hall of Fame in 2009; 75% of the vote was necessary for induction, and 5% was necessary to stay on future ballots.