Wood earned two wins in the Divisional Series against the Atlanta Braves and was the starter in Game 3 of the 2003 National League Championship Series, which the Cubs won in extra innings. However, the Cubs lost in seven games to the eventual World Series champion Florida Marlins. In the decisive Game 7, Wood hit the first home run by a pitcher in an NLCS game since another Cub, Rick Sutcliffe, did so in Game 1 in 1984. However, the Marlins won the game 9-6. Wood was the losing pitcher and the Cubs were eliminated.

The Chicago Cubs drafted Wood as the fourth overall selection in the 1995 Amateur Draft. He spent three years playing in the minor leagues. His best season in the minors came in 1996, when he posted a 10–2 record for the Daytona Cubs. He also played for the Triple-A Iowa Cubs. In 1997, he led all minor league pitchers in walks, with 131.

Wood made his first appearance in the major leagues on April 12, 1998. In his fifth career start, on May 6, he threw a one-hit, no-walk, 20-strikeout shutout against the Houston Astros in Wrigley Field, tying Roger Clemens’ record for strikeouts in a nine-inning game and breaking Bill Gullickson’s single-game rookie record of 18 strikeouts in 1980. Wood allowed only two baserunners: Ricky Gutiérrez on an infield single and Craig Biggio who was hit by a pitch with a count of one ball and two strikes. (Biggio had led the league in that category each of the previous three years.) Only seven balls reached fair territory. The Astros went on to lead the league in on-base-percentage, and all of the regulars were in the lineup, including the four who finished the season batting over .300. The performance garnered a game score of 105 – the highest number ever calculated for a pitcher in a nine-inning game.

On February 13, 1999, Wood and former high school teammate Kevin Walker were ticketed for urinating in a parking lot at 1:10 a.m. in Scottsdale, Arizona. Wood missed his initial court appearance and an arrest warrant was issued. He later pleaded guilty and paid a fine of $90.

Wood returned in 2000 and had an 8–7 record, but the following season, he returned to form. In 2001, Wood went 12–6 with a 3.36 ERA. He recorded a one-hit, 14-strikeout complete game shutout on May 25, 2001. On Aug. 3, 2001, he struck out nine batters and gave up only one run over eight innings to defeat Chan Ho Park and the Los Angeles Dodgers 2-1 to extend the Cubs’ lead in National League Central to 3.5 games. The following season, Wood finished 12–11 with a 3.67 ERA, and did not miss a start all year long, setting career highs with 213.6 innings pitched and 33 starts. He had 217 strikeouts in both seasons.

In 2003, Wood set career highs with 266 strikeouts, 14 wins (as part of a 14–11 record), a 3.20 ERA, and two shutouts. He threw the fastest fastball in the majors among starters, averaging 95.4 miles per hour. He also walked 100 batters and surrendered 24 home runs, also career highs, but was selected as a National League All-Star and helped lead the Cubs to the playoffs as one half of “Chicago Heat” along with fellow pitcher Mark Prior.

In 2005, Wood continued to struggle. On August 31, 2005, Wood underwent surgery and missed the remainder of the season. During Spring training in 2006, Wood suffered several injuries which required an additional surgery (on his knee). On May 18, 2006, Wood returned to the Cubs’ pitching rotation when he started and lost a home game against the Washington Nationals. In June, Wood returned to the DL with a sore shoulder. The following month, the Cubs announced that Wood had sustained a partially torn rotator cuff which was likely to keep him from pitching again for the rest of the year. At the end of the 2006 season, the Cubs exercised their option on Wood’s contract and bought out the remaining $13M.

With his long history of injuries and inability to stay in the starting rotation, Wood accepted the Cubs’ offer to return as a relief pitcher in 2007. Wood attempted to sustain a regular throwing schedule and appearances during Spring training games. However, Wood was placed on the 15-day DL with soreness in his elbow and was then moved to the 60-day DL. Wood considered retiring if he continued to have pain in his throwing arm. He began playing catch on May 21. In his first rehab assignment in Cubs Rookie Ball, he struck out all three batters he faced. On July 24, he pitched 1 inning with the Single-A Peoria Chiefs, throwing 9 pitches. He made back-to-back appearances on July 26 and July 27, throwing his fastball between 92-94 mph with no discomfort.

He was generally limited to one inning per outing, not appearing in games on back to back days, though he did pitch in both halves of a double header on September 15. Wood was a major contributor to the Cubs’ NL Central Division Championship down the stretch in late September, earning a win and 8 holds. Wood filed for free-agency on November 11, 2007, though he suggested that he wanted to remain in pinstripes for the 2008 season. Despite multi-year offers from other teams, Wood agreed to a one-year, $4.2 million deal with the Cubs.

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.

Cubs fans showed their appreciation for him by giving him a standing ovation when the Cleveland Indians played at Wrigley Field on June 19, 2009. During the 2010 season, Wood was placed on the disabled list until May 8 due to an upper back muscle strain. On July 17, 2010, Wood was placed on the disabled list for the 14th time in his major league career, this time due to a blister on his right index finger.

Wood was traded from the Cleveland Indians to the New York Yankees on July 31, 2010 for Andrew Shive, Matt Cusick, and cash. With the Yankees, he went 2-0 with a 0.69 ERA in 24 games, including 21 straight scoreless appearances, and served as the bridge to Mariano Rivera in the 2010 postseason. During the 2010 postseason, Wood had a 2.25 ERA appearing in 7 games overall. The Yankees won the 2010 ALDS against the Minnesota Twins in 3 games but lost to the Texas Rangers in 6 games of the 2010 ALCS.

On December 16, 2010, Wood agreed to a one-year deal worth $1.5 million with the Cubs. Wood reportedly turned down offers for long-term deals from several other teams worth more money due to his desire to keep his family in Chicago. Wood re-signed with the Cubs on January 13, 2012 for a 1-year, $3 million deal with a team option for 2013.

On May 18, 2012, Wood retired, striking out the only (and therefore final) batter he faced, Dayán Viciedo of the Chicago White Sox. The fans at Wrigley Field gave Wood a long standing ovation as his son, Justin, ran out to greet him as he exited the field. On his baseball career: “I had fun, I had a blast”, Wood said. “I wouldn’t trade anything in.”

On June 24, 2013, while paddleboarding in waters in Chicago, Wood happened upon a corpse floating in Belmont Harbor. He immediately reported the grisly discovery to local authorities, who determined the deceased to be a 40-year-old man who had been reported missing by a North Side nursing home days earlier.