In 2004, Floyd was a non-roster invitee to spring training. He began the season with the Reading Phillies (AA) and did not allow any runs in his first 4 starts, allowing only 1 runner to make it past 2nd base. He was named the Phillies farm system Minor League Pitcher of the Week, as well as Phillies Minor League Pitcher of the Month for April (2–0, 0.00 ERA). He was promoted to the Scranton/Wilkes-Barre Red Barons (AAA) in July and made 5 starts before having his contract purchased by Phillies as a September callup.

In 2005, Floyd made the team out of spring training and pitched strongly against the St. Louis Cardinals lineup, but struggled thereafter and was demoted to the minors, where he continued to struggle for the 2005 season. He came to 2006 spring training with barely a consideration and pitched his way into the Phillies rotation as the #4 pitcher, pushing Ryan Franklin to the bullpen. However, once again Floyd struggled, with a 4–3 record and a 7.29 ERA, and on June 2, was demoted to Scranton/Wilkes-Barre for the second straight year.

On December 6, 2006, Floyd was traded with Gio González to the Chicago White Sox for Freddy García. Floyd was expected to be handed the spot vacated by Garcia. However, since he pitched poorly during spring training, Floyd lost the spot and was optioned to Triple-A Charlotte.

On July 5, 2007, Floyd was recalled from Triple-A Charlotte by the White Sox. A day later, he pitched his first start as a South Sider in the second game of a doubleheader against Matt Garza of the Minnesota Twins, earning the loss and yielding 6 runs in 6 innings of work; the White Sox would eventually be blown out of the game, losing 12–0 to the rival Minnesota Twins.

In 2008, Floyd emerged as a legitimate and solid starting pitcher at the back end of the White Sox rotation. Showing flashes of brilliance, he carried near-no-hitters against visiting Detroit (April 12) and Minnesota (May 6) into the eighth and ninth innings, respectively, and also retired 12 consecutive Baltimore Orioles to start an eventual 6–5 extra inning loss in Baltimore on April 17. He finished the regular season with a 17–8 record, with his final win coming in a game in which the White Sox beat the Detroit Tigers to force a one-game playoff with the Twins to determine the Central’s winner. During 2008 he led the majors in stolen bases allowed, with 37 – 9 more than the next closest pitcher.

Floyd re-signed with the White Sox on March 22, 2009; his 4-year contract was worth $15.5 million. During the 2009 season, Floyd started 30 games, posting an 11–11 record and an ERA of 4.06, while cutting the number of stolen bases he allowed to 14.

Floyd only started 5 games with a 0-4 record and an ERA of 5.18 during the 2013 season. On April 28, 2013, Floyd was placed on the 15-day disabled list due to elbow soreness. After an MRI revealed that the elbow had a torn flexor muscle and UCL. Floyd underwent Tommy John surgery on May 7, 2013 and was shut down for the rest of the 2013 season. The surgery required from 12–14 months to fully recover.

Floyd became a free agent at the end of the 2013 season, and he signed a $4 million contract with the Atlanta Braves on December 16, 2013. In June 2014 Floyd suffered a fractured olecranon, missing the rest of the season. Alex Wood replaced Floyd in the rotation.

Floyd signed a one-year deal with the Cleveland Indians on December 16, 2014, but was subsequently placed on the 60-day disabled list on April 5, 2015 after injuring his pitching elbow during spring training. Floyd made his Indians debut on September 2, 2015, pitching a single inning of relief.

On February 6, 2016, Floyd signed a one-year, $1 million contract with the Toronto Blue Jays. Floyd entered spring training in competition for the fifth starter role with Aaron Sanchez, Drew Hutchison, and Jesse Chavez. On March 28, it was announced that Sanchez would be the team’s fifth starter, and Floyd would begin the season in the bullpen. Floyd left a game against the White Sox on June 25 with a shoulder injury, and was placed on the 15-day disabled list after the game. On June 28, it was determined that he had torn his right lat muscle and would miss 8–12 weeks recovering. Floyd remained on the disabled list for the rest of the 2016 season. He finished the season with a 2–4 record, 4.06 ERA, and 30 strikeouts in 31 innings pitched.

On January 5, 2017, Floyd signed a minor league contract with the Blue Jays that included an invitation to spring training. He did not appear in any spring training games, and was released on April 5.