Wood, along with Bob Howry and Carlos Mármol, competed for the role as the Cubs' closer after Ryan Dempster was moved to the starting rotation. After posting a 2.84 ERA in the spring, Wood won the job. He recorded his first career save April 3, 2008 with a win over the Brewers. Wood recorded 34 saves in 39 opportunities, 82 strike-outs and a 1.12 WHIP. He was selected to the 2008 MLB All-Star Game as a relief pitcher on July 6, 2008 along with six other teammates.
Wood was placed on the 15-day DL on July 24, 2008 with a blister on his right index finger.
On November 13, 2008, after acquiring closer Kevin Gregg from the Florida Marlins, Cubs general manager Jim Hendry announced that the organization did not plan to re-sign Wood. He had previously requested a multi-year contract with the team, but was deferred due to financial reasons. Wood stated he wished to remain with the Cubs, but also wanted to continue playing baseball.
On December 13, 2008, Wood signed a two-year contract with the Cleveland Indians.