He played in Major League Baseball for the St. Louis Cardinals (1974–79), San Diego Padres (1980), New York Yankees (1981–83), Houston Astros (1983–85) and Chicago Cubs (1986–88).

Mumphrey made his major league debut on September 10, 1974, the day after his 22nd birthday, as a pinch runner for Keith Hernandez.

Playing the Chicago Cubs, he reached on an error by second baseman Billy Grabarkewitz, and came around to score on Marc Hill's bases loaded walk.

He was batting .338 in nineteen games for Tulsa in 1976 when he was brought up to fill in for center fielder Bake McBride, who was having knee trouble.

[5] The next day, Giants pitcher John Montefusco faked a throw to third, and spun around to pick Mumphrey off first base.

Originally, the center field job fell to Bosetti and switch hitter Tony Scott.

He batted .305 with thirteen doubles and seven triples through the All-Star break to become the Cardinals' center fielder for the second half of the season.

He also led major league center fielders with eleven errors, the most impactful of which came on August 15 in an extra innings game with the Astros.

With two outs in the twentieth inning, Mumphrey misplayed a Terry Puhl fly ball into a three base error that scored two runs.

[16] After the season "Trader" Jack McKeon sent Mumphrey and John Pacella to the New York Yankees for Ruppert Jones, Joe Lefebvre and minor league pitchers Tim Lollar and Chris Welsh.

[21] In the 1981 American League Championship Series with the Oakland Athletics, he went 6-for-12 with three walks in the Yankees' three-game sweep.

[22] Mumphrey singled and came around to score on Bob Watson's home run in his first at bat of the 1981 World Series against the Los Angeles Dodgers.

[24] He returned for game six, got a single in the third, but struck out in the final inning of the Dodgers' World Series victory.

[28] Starting in center field again, Mumphrey ignited one of the Astros' greatest comebacks of the season shortly after joining his new club.

On August 23, with the Astros trailing the Pirates 5–1, Mumphrey led off the ninth inning with a single off starter John Candelaria.

Following Alan Ashby's single, Denny Walling hit a three-run home run to chase Candelaria from the game.

On May 14, 1984, Mumphrey singled in the bottom of the ninth off Pirates closer Kent Tekulve for his one thousandth major league hit.

He was struck out by the Detroit Tigers' Jack Morris to end the fourth inning in his only at bat.