Silva signed with the Philadelphia Phillies as an amateur free agent in 1996. He made his Major League debut in 2002, pitching the entire season out of the bullpen. Silva appeared in 68 games for the Phillies, going 5-0 with a 3.21 ERA and 41 strikeouts. In 2003, he went 3-1 despite an ERA of 4.43 in 62 games and 1 start.

In December 2003, the Twins acquired Silva from Philadelphia along with Nick Punto and Bobby Korecky in exchange for Eric Milton, who had been a staple of the Minnesota rotation since 1998.

With the Twins, Silva made a successful conversion from reliever to starter, in one of the biggest surprises in the 2004 season. He posted a 14–8 mark in 203 innings pitched and finished second in the rotation behind Cy Young winner Johan Santana. In 2005, he induced more double plays (34) than any other pitcher in the majors. In 2005, he set the record for fewest walks allowed per 9 innings in the modern era with an average of .43 BB/9 innings. On May 20, 2005, Silva set a record since 1957 for the fewest pitches thrown (74) in a nine-inning complete game.

In May 2006, Silva was demoted to the bullpen after struggling through the beginning of the season. In June, he re-entered the rotation when the struggling # 5 starter, Scott Baker, was demoted to the Twins’ Triple-A team in Rochester. He gave up a major-league-worst 1.90 home runs per 9 innings, giving up 38—more than any other major league pitcher, and had a major-league-worst batting average against of .326. In both 2005 and 2006 Silva gave up more home runs than walks in each season becoming one of 15 pitchers that qualified for the ERA title to accomplish.

Through 2006, Silva posted a 42–32 record with 306 strikeouts and a 4.35 ERA in 743 innings. In 2007, Silva started as the fifth starter behind Johan Santana, Boof Bonser, Ramón Ortiz, and Sidney Ponson. In his final season with the Twins, Silva finished 13-14 in 33 starts with a career high 89 strikeouts.

Silva allowed Frank Thomas’s 500th career home run on June 28, 2007 at the Metrodome.

On December 20, 2007, he signed a four-year contract with the Seattle Mariners believed to be somewhere between $44 million and $48 million.

In his first full season as a Mariner, Silva posted the worst ERA for a full-time starter in 2008 with a 6.46 ERA in 28 starts. He also spent time on the DL with a sore elbow. He finished 4-15 as he managed to win just one game after the month of April.

On December 18, 2009 Silva was traded along with $9 million to the Chicago Cubs for outfielder Milton Bradley. Silva appeared to have turned his career around early in 2010, becoming the first Cubs starter since 1967 to begin a season with an 8–0 record. However, his success was very limited for the remainder of the season, and he was cut from the Cubs towards the end of spring training in 2011.

On April 9, 2011, the New York Yankees signed Silva to a minor league deal. He was released on July 2.

On January 3, 2012, Silva signed a minor league deal with the Boston Red Sox. He was released on March 17.