He pitched for 16 years in Major League Baseball for the Cincinnati Reds (1970–1971), Cleveland Indians (1972–1974), Chicago Cubs (1975), Detroit Tigers (1977–1985), and Seattle Mariners (1986).

In 16 major-league seasons Wilcox appeared in 394 games, including 283 as a starter, and compiled a 119–113 win–loss record with a 4.07 earned run average (ERA) and 1,137 strikeouts, 2,0162⁄3 innings pitched, and 770 bases on balls.

[2][4] Wilcox graduated from high school in June 1968 and had a scholarship offer from the University of Oklahoma.

[2] He was selected that same month by the Cincinnati Reds in the second round (33rd overall pick) of the 1968 Major League Baseball Draft.

[5] Wilcox next split the 1969 season between the Florida Instructional League Reds and the Tampa Tarpons.

He made his major-league debut on September 5, pitching five innings and getting the win against the San Diego Padres.

[1] He qualified for the Reds' postseason roster and was the winning pitcher (three scoreless innings) in Game 3 of the 1970 National League Championship Series.

He was also the losing pitcher in Game 2 of the 1970 World Series where he gave up two earned runs in two innings pitched.

[5] On December 6, 1971, the Reds traded Wilcox to the Cleveland Indians in exchange for outfielder Ted Uhlaender.

[1] On February 25, 1975, the Indians traded Wilcox to the Chicago Cubs in exchange for outfielder Brock Davis and pitcher Dave LaRoche.

"[8] He spent the remainder of the 1976 season with the Evansville Triplets, the Tigers’ Triple-A club in the American Association.

[8] Wilcox credited "throwing bowling balls with rescuing his major league pitching career.

"[11] Wilcox spent the first part of the 1977 season in Evansville, compiling a 9–4 record in 14 starts with a 2.44 ERA and 69 strikeout.

[12] Wilcox was also the Tigers' union representative during these years, including during the 1981 Major League Baseball strike.

[12] On April 20, 1982, on his 32nd birthday, Wilcox threw a one-hit victory against the Kansas City Royals.

"[14] Wilcox won 31 games for the Tigers during the 1970s, ranking him fourth on the club, behind Mickey Lolich, Joe Coleman, and John Hiller.

The fans in Chicago gave Wilcox a standing ovation at the start of the ninth inning and booed when Hairston got the hit.

[1] Catcher Lance Parrish attributed Wilcox's 1984 surge to confidence: I've been trying to figure out all season why Milt's been so much better this year.

[18]In the postseason, the Tigers swept the Kansas City Royals in the American League Championship Series.

On October 5, Wilcox won the decisive Game 3, striking out eight batters in eight innings of shutout baseball.