Pérez was called up to the majors for the first time on August 10, 2011. On August 29, Pérez hit his first major league home run against Max Scherzer of the Tigers. In that game, Pérez was a triple away from hitting the cycle. In his rookie year, he batted .331 with 3 HRs and 21 runs driven in in 39 games.
On February 27, 2012, Pérez signed a five-year, $7 million extension that includes three club options. He is under team control through 2019. He could earn up to $26.75 million if he reaches all of his incentives and all of his options are picked up. The extension covers his pre-arbitration seasons, two of his three arbitration eligible years, and, if all of his options are picked up, his final arbitration year and his first two years of free agency. Pérez will earn $.75 million in 2012, $1 million in 2013, $1.5 million in 2014, $1.75 million in 2015 and $2 million in 2016. His options are $3.75 million in 2017, $5 million in 2018 and $6 million in 2019.
While catching a bullpen session before a spring training game in 2012, Pérez tore his right meniscus. He did not return until July 2. Overall, he hit .301 with 11 homers and 39 RBIs in 79 games played.
On July 16, 2013, he was the catcher for Mariano Rivera in Rivera's final All-Star Game before retirement. After the season, Perez was awarded the American League Gold Glove Award for his defense at catcher.