The Pittsburgh Pirates selected Whitson in the sixth round of the 1974 Major League Baseball draft out of Unicoi County High School in Erwin, Tennessee.

His one win came on September 17, when he made an emergency start against the Montreal Expos in place of Jerry Reuss, who was a late scratch.

He made seven starts with Columbus, however, was used strictly out of the bullpen by Pirates manager Chuck Tanner, going 5–6 with a 3.27 ERA as a relief pitcher, and earning four saves.

The Pirates were in fourth place, 6+1⁄2 games back of the Montreal Expos on June 28, 1979, when Whitson was traded along with Al Holland and Fred Breining to the San Francisco Giants for Bill Madlock, Lenny Randle and Dave Roberts.

Injuries and the 1981 Major League Baseball strike limited Whitson to just 22 starts in 1981, resulting in a 6–9 record and 4.02 ERA.

He made his first start for the Indians in the first game of a double header with the Milwaukee Brewers on August 1, 1982, pitching six innings and giving up just one run to earn the win.

Despite his ejection, he reappeared on the field shirtless and wielding a bat while defending his teammates from unruly Braves fans in the ninth during the second of two late-inning bench-clearing brawls.

The Padres actually came back and won the game, as Andy Hawkins and Craig Lefferts both pitched brilliantly out of the bullpen, holding the Tigers to two hits and no runs from that point forward.

[13] Whitson became a free agent following the 1984 season, and signed a five-year contract with the New York Yankees worth $4.4 million with a sixth-year option.

He began receiving verbal abuse and hate mail, and refused to let his wife, Kathleen, attend home games at Yankee Stadium.

[15] On June 11, 1985, after giving up five hits and one run against the Toronto Blue Jays in Yankee Stadium, Whitson retired the next 19 batters he faced.

[22] Tommy John thought that Whitson had trouble handling the intense pressure and media coverage of New York.

[23] Used primarily as a starter, Whitson went 11–20 with a 4.89 ERA his first season and a half back in San Diego, largely due to the fact that he led the league in home runs allowed in 1987 with 36.