After his 2003 call up to the major leagues, Peralta began to draw widespread attention for his hitting with the Aeros and Bisons.

[7] Peralta made his Major League debut with Cleveland on June 12, 2003, appearing in the eighth inning as a defensive replacement for Casey Blake at third base.

[9] Peralta became Cleveland's full-time starting shortstop early in 2005 and batted .292 with 24 home runs and 78 RBI in 141 games.

[10] On March 10, 2006, Peralta agreed to a five-year, $13 million contract with an option for a sixth year to stay with the Indians until the 2011 season.

[9] At the start of spring training in 2007, it was revealed that Peralta suffered from vision problems in 2006 and had corrective LASIK eye surgery to deal with it.

[9] After eliminating the New York Yankees in the ALDS, the Indians advanced to the 2007 American League Championship Series to face the Boston Red Sox.

[15] Peralta hit .259 with two home runs and 8 RBI in the seven-game series, which was eventually won by the Red Sox.

[9] Peralta hit his first career inside-the-park home run against Tigers pitcher Andy Oliver on July 18, 2010.

The home run came on a play in which outfielder Ryan Raburn crashed through the bullpen door attempting to catch the ball.

[23] Peralta finished the regular season with a career-high .299 batting average and collected 21 home runs and 86 RBI in 146 games.

Playing a full season at shortstop for the first time since 2008, he committed just seven errors in 608 chances for a career-best .988 fielding percentage.

[28] On June 20, 2013, Peralta hit a walkoff two-run home run off Boston Red Sox closer Andrew Bailey to secure the Tigers' victory, 4–3.

[9] Because Detroit had acquired rookie shortstop José Iglesias from the Boston during the suspension, manager Jim Leyland installed Peralta mainly in left field for the remainder of the season and playoffs.

[34][35] The Tigers, including general manager Dave Dombrowski, expressed exoneration of Peralta's breach following the suspension.

[36] Despite derisive chants from fans and actions such as the San Francisco Giants leaving similar violator Melky Cabrera off their playoff roster during their World Series-winning season, the Tigers saw the 50-game suspension as sufficient punishment.

[37] With the Tigers down 3–0 and facing elimination against the Athletics in Game 4 of the American League Division Series (ALDS), Peralta connected for a three-run home run in the fifth inning.

[38] The Tigers eventually won the ALDS but lost to the Red Sox in the American League Championship Series.

Arizona Diamondbacks pitcher Brad Ziegler spearheaded a cacophony of complaints that the 50-game suspension was not enough of a deterrent, because he viewed that it failed to prevent players who violated the collective bargaining agreement's banned substances use policy to receive compensation for their performances equal to those who had not been found to violate the policy.

Cabrera had signed with the Toronto Blue Jays for two years and $16 million following his suspension in 2012; however, little protest had arisen from those relatively modest figures.

"[44] New teammate and Cardinals outfielder Matt Holliday, an outspoken critic of performance-enhancing drugs (PED), declared indemnity.

It also gave him six home runs for the month, surpassing Édgar Rentería's club record of five in April he set for shortstops in 2000.

[47] Peralta surpassed another team record for shortstops Rentería set in 2000, hitting his 17th home run of the season on August 20.

[49] With the second-place Pirates just a game behind in the standings with two left to play for the season, Peralta drove in the go-ahead run in the 10th inning against the Diamondbacks as part of a three-RBI night.

[53] In counting and rate defensive statistics among NL shortstops, he finished second in double plays turned (98), and fifth in fielding percentage (.981), putouts (191), and assists (418).

[62] Peralta finished the season with a .275 batting average, 17 home runs, 71 RBI, 26 doubles, and 159 hits in 155 games played.

[9] In the 2015 National League Division Series, Peralta hit just .143 with an RBI as the Cardinals were defeated by the Chicago Cubs in four games.

[63] While fielding a ball during spring training on March 7, he damaged an ulnar collateral ligament in his left thumb.

[65] He began a rehabilitation assignment with the Single-A Peoria Chiefs on May 20, 2016,[66] and the club activated him for game action before a series against Cincinnati on June 7.

[67] The Cardinals placed Peralta back on the disabled list on July 19 due to swelling in the left thumb, although that injury appeared unrelated to the torn ligament and an MRI had revealed no structural damage, per Mozeliak.

[68] Due to the emergence of shortstop prospect Aledmys Díaz, the Cardinals began to shift Peralta over to third base upon his return.