After working with former MLB pitcher Dennis Martínez to improve his change-up, Padilla was signed as an international free agent by the Arizona Diamondbacks on August 31, 1998. He debuted in the minor leagues in, playing for the Class-A Advanced High Desert Mavericks and earning a promotion to the Class-AAATucson Sidewinders. Padilla made his Major League debut on June 29 against the Cincinnati Reds, pitching in the ninth inning and giving up four hits and three runs without recording an out, getting the loss and a blown save for the effort. Padilla appeared in four more games in 1999. He also appeared in 27 games in relief for the Diamondbacks in 2000, finishing 2–1 with a 2.31 ERA, with his first win coming on May 9 against the Los Angeles Dodgers.
Philadelphia Phillies
On July 26,, Padilla was traded from the Diamondbacks to the Philadelphia Phillies along with three other players for pitcher Curt Schilling. He was moved to the starting rotation in and made his first start on April 3 against the Atlanta Braves, working six innings and picking up the win. He finished the season 14–11 with a 3.28 ERA in 32 starts and was selected to appear in the All-Star Game. He battled injuries during the and seasons, posting a combined win–loss record of 16–19. After posting a 4.71 ERA and a 1.50 WHIP during the 2005 season, Padilla was traded to the Texas Rangers for Ricardo Rodríguez.
Texas Rangers
During the 2006 season, he also came under fire for his "lack of control" on the mound. Padilla caused a controversy in Chicago when he twice hit White Soxcatcher A. J. Pierzynski, and later in the season again caused a benches-clearing brawl against the Angels when he repeatedly threw at Angels batters, showing particular interest in slugger Vladimir Guerrero. On September 16,, Padilla hit Oakland AthleticsoutfielderNick Swisher after two pitches earlier in the plate appearances were inside that almost hit Swisher. Swisher then charged the mound starting a brawl and resulting in both players getting ejected. He also has history of hitting former teammate Mark Teixeira on June 6, 2009. In 2006, he and Kevin Millwood won 15 games; a total not matched by a Rangers pitcher until Scott Feldman surpassed it in 2009. His 11 road victories in 2008 matched a club record set by Rick Helling, later surpassed by Scott Feldman. On July 22, 2009, Padilla tested positive for swine flu, and was believed to be the first major U.S. athlete to catch the disease. On August 7, 2009, Padilla was designated for assignment by the Rangers after going 8–6 with a 4.92 ERA in 18 starts. Ten days later Padilla was given his release. He was released because he was "regarded as a disruptive clubhouse presence."
Los Angeles Dodgers
On August 19, 2009, Padilla signed a minor league contract with the Los Angeles Dodgers. He made one start with the AAA Albuquerque Isotopes and then was activated on August 27 to start for the Dodgers against the Colorado Rockies. He made seven starts for the Dodgers in August and September, finishing with a record of 4–0 and a 3.20 ERA. On October 10, 2009, Padilla was the starting and winning pitcher in the clinching Game 3 of the National League Division Series against the St. Louis Cardinals, pitching seven innings of shut-out ball. He also pitched well in Game 2 of the NLCS against the Philadelphia Phillies, working 7.1 innings and only allowing one run ina game the Dodgers eventually won. However, he picked up the loss, giving up 6 earned runs in 3 innings of work, in the deciding Game 5, allowing the Philadelphia Phillies to advance to the World Series for the second straight year. On November 3, 2009, Padilla was injured when he was accidentally shot in the leg at a shooting range in Nicaragua. It was not a serious injury. On January 21, 2010, Padilla re-signed with the Dodgers, a one-year, $5.025 million deal, with $1 million of that in the form of a signing bonus. On March 25, 2010, the Dodgers announced that Padilla would be their opening day starter for the 2010 season. Due to a number of recurring injuries, Padilla only was able to start 16 games for the Dodgers in 2010, finishing 6–5 with a 4.31 ERA. His best performance was a complete game shutout against the San Diego Padres on August 4. He made just three more starts after that before he was shut down for the season. After the season, Padilla re-signed with the Dodgers on a one-year, incentive-laden deal. He was injured in spring training in 2011 and began the season on the disabled list, rejoining the team on April 23 as a reliever. In his new role, he picked up his first save since 2000 in a 10 inning game against the Florida Marlins on April 27. He became the Dodgers closer for a brief time after Jonathan Broxton was placed on the disabled list. However, he also wound up on the disabled list on May 14. He was first shut down with a forearm injury and later with neck problems, which required surgery. He was unable to return to the Dodgers in 2011, appearing in only 9 games, pitching 8.2 innings with a 4.15 ERA and 3 saves. This was the fewest appearances for Padilla since his first season, and the first year he did not start any games since 2001 with the Phillies.
Boston Red Sox
On January 16, 2012, Padilla signed a minor league deal with the Boston Red Sox that included an invitation to spring training. He earned $1.5 million when he was promoted to major league level. Padilla made the 25-man roster and pitched out of the bullpen.
Padilla has a wide variety of pitches: a fastball, a curveball, a sinker, a slider, a changeup, and an eephus pitch. The fastball is his main pitch: it tends to reach speeds of about 92-94 mph. However, he is also one of the few pitchers in baseball to throw an eephus pitch, a slow curve that travels about 55 mph. Padilla rarely throws this pitch consecutively, though. He has never led his league in walks, but tends to hit a lot of batters: his total of 106 hit batters is tied for 67th all-time, and he led the American League in hit batters in 2006.
