Ramírez made his MLB debut on March 31, 2008. He recorded his first major league hit on April 2, a single off Cleveland Indians reliever Jorge Julio. Ramírez hit his first major league home run on May 16, off San Francisco Giants reliever Billy Sadler.
Ramírez hit his first career grand slam on July 22, 2008. On September 19, Ramírez hit his third grand slam of the season off of pitcher Brian Bannister of the Kansas City Royals, tying an American League rookie record set by Shane Spencer of the New York Yankees in 1998. It was the White Sox's eleventh grand slam of the season, equaling the previous club record from 2006. On September 29, Ramírez hit his fourth grand slam of the season, setting a major-league single-season record for a rookie, off of Detroit Tigers pitcher Gary Glover in an 8–2 Sox victory to qualify the Sox for a one-game tiebreaker against the Minnesota Twins for the AL Central title. This also broke the team record for most grand slams in a single season.
During his first season in the Majors, Ramírez excelled both offensively and in the field, despite primarily playing second base instead of his customary shortstop position. Over 136 games, he posted a .290 batting average, hitting 21 homers and driving in 77 runs. He finished in second place in the voting for American League Rookie of the Year honors, losing to Evan Longoria of the Tampa Bay Rays.Ramírez led the major leagues in grand slam home runs in 2008, with four, and also swung at 59% of all pitches he saw for the season, also the most in the majors.