A prospect in the minor leagues, 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, 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. To date, Wood and Bob Feller are the only two pitchers to strike out their age in one game (at age 17, Feller struck out 17 batters in one game in 1936). Wood allowed only two baserunners: an infield single by Ricky Gutiérrez, and hit Craig Biggio. The single, off third baseman Kevin Orie's glove, was close enough that some fans lobbied to have it changed in scoring to an error, which would have given Wood a no-hitter. The game is considered by many to be the most dominant pitching performance in the history of baseball.
Wood finished the 1998 season with a 13–6 record; despite missing the last month of the season with elbow soreness, he easily won the National League Rookie of the Year award. He pitched one game in the playoffs, losing against the Atlanta Braves.