Candiotti, nicknamed "The Candy Man" or simply "Candy",^[2][3] was not drafted by any major-league team despite his success at Saint Mary's College. He got a shot when he traveled to Victoria, British Columbia, for a tryout with the independent Victoria Mussels of the Northwest League in 1979. Candiotti won five games that year for a Victoria team that lost out on the pennant by percentage points to the Walla Walla Padres. "I had no place to stay", Candiotti recalled years later. "For a week, I stayed in the locker room. After that, I stayed with a buddy. I slept on the floor at his place. I didn't have any money. I didn't have a car or anything. There were even a couple of times when I slept on the field in my sleeping bag. It was that bad."^[4]

Following his only season in Victoria, the Mussels sold Candiotti to the Kansas City Royals in 1980. However, he never pitched for the Royals and was claimed in the Rule 5 draft by Milwaukee that year. Candiotti won his first four major-league starts with Milwaukee in 1983, including a complete-game shutout on August 25 against California. In his first three career starts, Candiotti pitched at least seven innings and gave up one earned run or none.^[4] After two seasons with the Brewers, Candiotti signed with Cleveland in 1985, where he enjoyed his most successful seasons.

With the woeful Indians of the 1980s, Candiotti had a record of 72-65 with only one losing season. His best season was 1988 when he went 14-8 with a 3.28 ERA and 137 strikeouts. Candiotti became known for his use of the knuckleball. According to former Texas Rangerspitching coach Tom House, Candiotti was only the 20th pitcher in major-league history to throw the knuckleball on a full-time basis.^[4]

In June 1991, Toronto acquired him from Cleveland in a trade to help in their playoff run, and Candiotti led the Blue Jays pitching staff with three complete games and a 2.98 ERA in 19 starts for a ballclub that had lost ace right-hander Dave Stieb to a season-ending injury. He was poised to win the ERA title as he had a major league-best 2.23 ERA on September 23 before giving up seven earned runs that night in California. In his first 16 starts with Toronto, his ERA was 2.21, a remarkable feat given the fact he threw the knuckleball and was working with two catchers (Pat Borders and Greg Myers) who had never caught that pitch before. "It was tough for Myers and Borders to adjust to me mid-season", Candiotti said. "Because I threw the knuckleball, I normally spent more time with my catchers than other pitchers. People don’t realize this—even the guys in the media—but not having spring training to work with them made a big difference."^[4]

He left the Blue Jays the following season to sign with Los Angeles where he pitched well for six years, hampered by poor run support. From 1992 to 1996, Candiotti's 3.57 ERA was fourth-best among National League pitchers with at least 900 innings pitched, behind only Greg Maddux (2.13), Tom Glavine (3.16), and John Smoltz (3.27), and 11th-best in the majors overall.^[4] He finished his career with the Indians before retiring in 1999.

At the time of his retirement, Candiotti ranked in the top 100 all-time in major-league history in starts and strikeouts. In 2001, he was named one of the Top 100 Greatest Indians in Cleveland history