In 2006, he was called up to the White Sox, and played in 21 games for the major league team. At the beginning of the 2007 season, Ryan was ranked by Baseball America as prospect No. 1 in the White Sox organization. That year he played in 15 games for the White Sox and 105 for the Charlotte Knights.
Oakland Athletics
On January 3,, the White Sox traded him, along with fellow prospects pitchers Fautino de los Santos and Gio González, to Oakland for outfielder Nick Swisher. He played in 8 games for the AAA Pacific Coast LeagueSacramento River Cats before being called up to the major league team, where he played in 116 games. Sweeney remained with the A's through 2011.
Boston Red Sox
On December 28, 2011, Sweeney and Andrew Bailey were traded to the Boston Red Sox for Josh Reddick, Miles Head and Raul Alcantara. Sweeney played in 63 games for the Red Sox during the 2012 season. On November 30, 2012 he was among those not offered a contract for 2013 by the Red Sox, and became a free agent. On January 26, 2013 the Red Sox signed Sweeney to a minor league contract which would pay him $1.25 million plus incentives if he made the major league team. Sweeney was signed to provide additional outfield depth when the team learned that Ryan Kalish required surgery and would miss at least part of the 2013 season. At the end of spring training in March, 2013, Sweeney was not added to Boston's major league roster. Rather than accept assignment to the minor leagues, he opted out of his contract and became a free agent.
Chicago Cubs
Sweeney signed a minor league contract with the Chicago Cubs on April 2, 2013. On May 6, 2013 the Cubs announced that Sweeney would be joining the major league team, with Dave Sappelt moving to the Cubs' Triple-A affiliate to make room on the Cubs roster for Sweeney. On May 8, 2013, Sweeney recorded his first hit as a Chicago Cub. Sweeney's first home run as a Cub came on May 19, 2013 at Wrigley Field. On June 15, Sweeney took over as the starting center fielder when David DeJesus sprained his shoulder running into a wall. On June 29, Sweeney fractured his rib while running into a wall making a catch against the Mariners. Brian Bogusevic then became the starting center fielder. On September 1, he returned to the Cubs, receiving the bulk of the starts in center field to end the year. In 2013, Sweeney played 70 games with the Cubs and hit.266/.324/.448 with 6 HR and 19 RBI. On October 8, Sweeney signed a two-year, $3.5 million deal with a $2.5 million option for 2016. He would earn $1.5 million annually, and the option had a $500,000 buyout. In 77 games in 2014, Sweeney hit.251 with 3 home runs and 20 RBI's. He went on the disabled list on August 27 with a left hamstring strain. Sweeney was designated for assignment by the Cubs on April 5, 2015, and released on April 7.
On December 17, 2015 the Minnesota Twins announced that Sweeney was one of several players who received a minor league contract and an offer to attend the Twins' spring training. He was released on March 25, 2016.
