In his first professional season as a 19-year-old with the Vancouver Canadians in Single-A, Harden had a 2–4 record in 18 games (14 starts), a 3.39 ERA, allowed only 47 hits and struck out 100 batters in 74 innings.

In 2002, Harden began the year with the Single-A Visalia Oaks of the California League and was very impressive in 12 starts, as he had a 4–3 record with an ERA of 2.91, and struck out 85 batters in 68 innings.

Harden came back and pitched a two-hit game against the Texas Rangers on July 14, in which he allowed no runs for 7+ innings.

One month later on August 14, Harden allowed only one hit, but received a no decision, en route to a 2–1 loss against the Minnesota Twins.

On August 19, Harden had a 10–5 record with an ERA of 2.63, until he injured his right shoulder, sidelining him until September 25, by which time the Athletics were already out of the playoff hunt.

He started off the 2007 season with a win against the Seattle Mariners, going 7 innings, striking out 7, and allowing two walks and two hits, before returning to the DL, on April 23.

In Harden's next start against his former teammate Tim Hudson and the Atlanta Braves, he pitched 7 innings only allowing 4 hits and a run while earning the win.

The Cubs traded Matt Murton, Eric Patterson, Sean Gallagher, and Josh Donaldson to Oakland for Harden and Chad Gaudin.

[6] He made his Cubs debut on July 12, against the San Francisco Giants, leaving the game with a 7–0 lead after pitching 5+1⁄3 scoreless inning and striking out 10.

Though the Cubs won 8–7, Harden earned a no decision after Carlos Mármol was unable to hold a five-run lead in the ninth.

He was put on the DL in June with a gluteal strain and returned to the rotation on July 31, pushing Scott Feldman to the bullpen.

Neftalí Feliz eventually gave up the first hit for the Twins with one out in the ninth, a single to catcher Joe Mauer.

[15] On July 30, 2011, Oakland agreed to trade Harden to the Boston Red Sox in exchange for Triple-A first baseman Lars Anderson and a player to be named later.

[16] That deal, however, fell through after the Red Sox front office reviewed Harden's medical records and determined that it was unlikely he would make it through the season without injury.

During the 2011–12 off-season, Harden underwent shoulder surgery and spent the entire 2012 season on free agency without signing for a team or playing a single game.

After a one year hiatus from baseball due to recovering from shoulder surgery, Harden signed a minor league contract with the Minnesota Twins on December 21, 2012.

Former Oakland Athletics catcher Adam Melhuse coined the term "spluckle"[22] (a combination of splitter and knuckleball) to refer to this innovative pitch.