That summer, the Baltimore Orioles made McDonald the first overall selection in the June draft. He had earlier been chosen by the Atlanta Braves in the 27th round of the 1986 draft, but decided to go to college at that time instead of signing. He signed with the Orioles on August 19, and on September 6, he made his major league debut. McDonald was the second member of his draft class to reach the majors, coming up three days after his Olympic teammate John Olerud.
McDonald joined the Orioles' starting rotation in 1990, and in his first major league start on July 21, he threw a complete gameshutout against the Chicago White Sox. At the end of the season, he finished eighth in Rookie of the Year voting, with the award going to catcherSandy Alomar, Jr. McDonald would go on to spend seven seasons with the Orioles, before leaving as a free agent in 1996 to join the Milwaukee Brewers. He never led his league in a major category, but ranked among the top 10 at various times in categories such as complete games, wins, ERA, WHIP, and strikeouts. McDonald was the first-overall draft pick to win his first three starts in Major League history, a feat which has been equalled by Gerrit Cole.
While with the Brewers, McDonald began to encounter shoulder problems, missing part of the 1997 season. He was traded to the Cleveland Indians that offseason, in a deal that brought Marquis Grissom and Jeff Juden to Milwaukee in exchange for him, Mike Fetters, and Ron Villone. McDonald would never pitch for the Indians, though, as an operation to repair his rotator cuff on February 26, 1998 proved unsuccessful. He was ultimately forced to retire, and the Brewers sent Mark Watson to Cleveland to resolve their obligation in the matter.
McDonald ended his career with a 78–70 record, 894 strikeouts, and a 3.91 ERA in 1,291⅓ innings pitched. He never pitched in the postseason.
McDonald was a guest analyst for Orioles telecasts on MASN in 2010 and an assistant coach for the Denham Springs High School softball team in Denham Springs, Louisiana. He also occasionally serves a guest color commentator on Orioles radio broadcasts.