In seven years of baseball in the Cuban National Series, Ramírez spent most of his time playing shortstop and outfield for Pinar del Rio. He had a batting average of .335 in Cuba, and led the league in 2007 with 20 home runs while posting a .338 average. Ramírez played center field for Cuba at the 2006 World Baseball Classic, collecting 6 hits in 16 at-bats and impressing US scouts in the process. He hits and throws right-handed.

In September 2007, Ramírez left Cuba to apply for citizenship in the Dominican Republic, and also apply to Major League Baseball to enter free agency, according to his agent, Jaime Torres. He auditioned for many baseball teams before coming to an agreement on a four-year contract with the Chicago White Sox on December 21, 2007.

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.

On May 5, 2014, Ramírez recorded his 1,000th career hit off of Chicago Cubs’ pitcher Justin Grimm in the 12th inning of the Crosstown Classic.

On November 4, 2015, the White Sox declined Ramírez’s $10 million option for the 2016 season, making him a free agent.

On January 22, 2016, Ramírez signed a one-year, $3 million contract with the San Diego Padres, with a $4 million mutual option for 2017. He broke up Steven Matz’s no-hit bid with a RBI single in a game against the New York Mets on August 14, 2016. Ramírez appeared in 128 games with the Padres, mainly at shortstop. He batted .240, with 5 home runs and 41 runs batted in. He was released by the Padres on September 4.

On September 8, 2016, Ramírez signed a major league deal with the Rays. He appeared in 17 games with Tampa Bay, tallying a .246 average, one home run, and 7 RBI. On November 3, Ramírez became a free agent.

On February 8, 2018, Ramírez signed with the Diablos Rojos del México of the Mexican Baseball League. He was released by the team on August 16, 2018.

In May 2020, Ramírez announced he was still seeking professional baseball opportunities. As of August 2020 he remains unsigned.