Wakefield began his Major League Baseball (MLB) career with the Pittsburgh Pirates, but is most remembered for his 17-year tenure with the Boston Red Sox, from 1995 until his retirement in 2012 as the longest-serving player on the team, earning a total of $55 million.

At Florida Tech, he was named the Panthers' team most valuable player as a first baseman in his sophomore and junior years.

[7] After a scout told him that he would never get above Double-A ball as a position player with his skills, Wakefield decided to re-invent himself as a knuckleball pitcher.

Wakefield advanced to Double-A in 1991, leading all Pirates minor leaguers in wins, innings pitched, and complete games when he went 15–8 with a 2.90 earned run average.

In his major league debut, Wakefield threw a complete game against the St. Louis Cardinals, striking out 10 batters while throwing 146 pitches.

[9] Down the stretch, Wakefield provided a boost for the playoff-bound Pirates, starting 13 games and compiling an 8–1 record with a 2.15 earned run average, a performance that won him the National League Rookie Pitcher of the Year Award from The Sporting News.

He recorded 15 saves before Derek Lowe emerged as the new closer and Wakefield returned to the starting rotation.

[1][17] Because of his success out of the bullpen, Wakefield was regularly moved from the position of relief pitcher to starter and back again over the next three seasons (2000–2002).

After retiring the side in order in the 10th, Wakefield gave up a home run to Aaron Boone on his first pitch of the 11th, sending the Yankees to the World Series.

[22] In the 2005 season, Wakefield led the Red Sox pitching staff with 16 wins and a 4.15 earned run average.

[26] On April 15, 2009, a day after the Red Sox bullpen was tasked with pitching over 11 innings of relief, telling manager Terry Francona not to remove him from the game.

On May 12, Wakefield recorded his 2,000th career strikeout against Vernon Wells of the Toronto Blue Jays in a 3–2 loss.

He joined Jamie Moyer, Javier Vázquez, and Andy Pettitte as the only active pitchers with at least 2,000 career strikeouts.

[37] On July 2, he surpassed Clemens for another record, this for starts at Fenway Park; he went eight innings to win 3–2 over the Baltimore Orioles.

[44] On May 11, 2011, Wakefield pitched 1+1⁄3 innings in relief as the Toronto Blue Jays defeated the Red Sox 9–3 at the Rogers Centre.

[46] It took Wakefield eight attempts to earn his 200th career win after his 199th, finally doing so in an 18–6 rout over the Toronto Blue Jays at Fenway Park on September 13, 2011.

The victory came at a time when the Red Sox were in dire need of wins, with the Tampa Bay Rays gaining substantial ground in the race for the American League wild card as Boston fell four games behind the New York Yankees in the AL East division standings.

[47] Boston eventually missed the playoffs by one game, and Wakefield ended the season at 7–8 with a 5.12 earned run average.

[1] For the 2012 season, Wakefield was offered a minor league contract, with an invitation to spring training, by the Red Sox.

Wakefield's primary pitch, the knuckleball, was thrown between 45 and 69 miles per hour (72 and 111 km/h) and had a great deal of variance in how much it "fluttered".

Throughout the first decade of his career, Wakefield followed a similar pattern: on April 27, 1993, he threw 172 pitches over 10+ innings in a game for the Pittsburgh Pirates against the Atlanta Braves.

[51] In his first two weeks with the Red Sox, Wakefield pitched a total of 33+1⁄3 innings, including two complete games in addition to a 7+1⁄3-inning emergency start on just two days' rest.

[54] Because of the difficulty of catching a knuckleball, the Red Sox sometimes carried a backup catcher who specialized in defense and who caught most or all of Wakefield's starts.

Josh Bard briefly caught Wakefield during the first month of the 2006 season, before Boston reacquired Mirabelli on May 1 after trading him to San Diego the previous offseason.

In 2011, Wakefield began the season in the bullpen and both Jarrod Saltalamacchia and Jason Varitek caught him when he entered games.

[59] In August 2015, Wakefield signed on as a spokesperson for Farmington Bank, making appearances at branch grand openings and in television, radio, and print advertisements.

[5] Wakefield partnered with the Franciscan Hospital for Children in Boston to bring patients to Fenway Park to share time with him on and off the field.

[66] Wakefield hosted an annual celebrity golf tournament, raising over $10 million for the Space Coast Early Intervention Center, a pre-school program for children with special needs.

[75] On April 9, 2024, the 2004 Red Sox reunited at Fenway Park for their 20th anniversary celebration on Opening Day against the Orioles.

The pregame ceremony was also dedicated to the Wakefields, along with Red Sox president Larry Lucchino, who died of heart failure on April 2 at the age of 78.