He started the 2006 season on the 15-day disabled list with a strained hamstring before returning to the team going 1–2 with a 5.16 ERA with the Rangers before getting optioned to Triple-A on June 1. While in the minors, he went 1–0 with a 2.45 ERA with two saves, and in 11 innings, he struck out 17 and walked five in nine appearances. After being recalled July 18, Wilson ended the season strong, posting second half numbers of a 3.29 ERA in 24 2/3 innings and 27 appearances and ending the season as the team's top left-handed setup man, posting a 2–4 record and 4.06 ERA overall for Texas. He proved especially tough against lefties, with an ERA of 1.77 with 19 strikeouts in 20⅓ innings.

At the end of April, Wilson was leading the Rangers rotation with an ERA of 1.76 after 4 starts, fourth best in the AL. On May 7 against the Kansas City Royals, Wilson threw a complete game winning 4–1. It was Wilson's second credited complete game of the year and career, the previous being a rain-shortened six-inning loss to the Yankees. Wilson set 2 club records after his May 13 start against the A's with the most consecutive innings without a home run and most consecutive quality starts to start a season. Wilson gave up his first home run on May 19 against the Angels' Torii Hunter after 87 2/3 innings dating back from 2009. Wilson's consecutive quality starts also ended in the same game.

After attending Fountain Valley High School (graduating in 1998), Wilson played at Santa Ana College where in 2000 he was named the MVP of the Orange Empire Conference, and awarded the California Junior College Co-Player of the Year award. Wilson played outfield, first base, starting pitcher, and relief pitcher at Loyola Marymount University during the 2001 season.

After starting the 2001 season in Pulaski of the Appalachian League he was promoted to Class A with the Savannah Sand Gnats. He moved through High-A Charlotte (Florida State League) and into Double-A Tulsa (Texas League) by late 2002.

For 2003, Wilson returned to Double-A with Frisco RoughRiders of the Texas League, earning Pitcher of the Week honors in May. His up and down season was cut short due to injury which resulted in season-ending Tommy John surgery on August 12.

After missing all of 2004 due to the elbow injury, Wilson was able to return to Double-A in 2005 before being called up to the majors later that season. He posted a 1–7 record and 6.94 ERA in 24 games during his rookie campaign with the Rangers. Later in the season, Texas placed him in the bullpen full-time where he went 1–2 with a 2.73 ERA in 18 relief appearances.

Following the trade of Éric Gagné, Wilson was used to close out games for the Rangers in 2007 converting his first 11 consecutive chances. Overall, he finished with career bests in: ERA (3.03), appearances (66), innings (68.1), strikeouts (63), WHIP (1.21), holds (15), and opposing batting average (.208).

He was named the Rangers closer for the 2008 season. He had a 6.06 ERA and converted 24 of 28 save opportunities.

In 2009, Wilson returned to role of set-up man as Frank Francisco was named the closer. He set new career bests in: wins (5), innings (73.2), appearances (74), ERA (2.81), strikeouts (84), K/BB ratio (2.61), holds (19), home runs allowed (3) as well as recording 14 saves throughout the year and set a team record for the lowest home ERA for a single season (0.67).

Wilson races racecars in his free time, and has mentioned he aims to be a professional racer after his baseball career; he also is highly interested in cars, having a collection of Porsches as well as a custom painted McLaren P1. Wilson won the E1 class in the 2010 25 Hours of Thunderhill. He races a Mazda MX-5 in club races and owns a race team that competes in the professional Global MX-5 Cup series.

On December 8, 2011 Wilson agreed to a five-year, $77.5 million deal with the Los Angeles Angels of Anaheim. This deal came only hours after Albert Pujols signed a record breaking ten-year, $250 million deal with Anaheim. The contract became official on December 10.

On May 22, 2012, Wilson and Ernesto Frieri pitched a combined one-hit shutout against the Oakland Athletics in Oakland, a place Wilson said that he strongly disliked pitching while with the Texas Rangers. Wilson struck out seven and allowed two walks while giving up a single. He was selected to the All Star game in 2012 after going 9-5 with a 2.43 ERA for the Angels. He finished the season with a 13-10 record in 34 starts. He followed the 2012 season with another successful season, winning a career high 17 games while lowering his ERA from the prior season to 3.39.

Wilson married Brazilian model Lisalla Montenegro on December 15, 2013 in Laguna Beach, California. They have two daughters.

Despite the team making the playoffs in 2014, Wilson did not have a good season, finishing with an ERA of 4.51 and leading the majors in walks with 85. Due to his high pitch counts, Wilson averaged less than 6 innings per start. Wilson's season was cut short in 2015, starting only 21 games before going out with an elbow injury in early August. He opted for elbow surgery.

He started the 2016 season on the disabled list recovering from elbow and shoulder surgery. On July 5, it was announced that Wilson would undergo season-ending shoulder surgery, ending his career.