Grandal was drafted by the Cincinnati Reds 12th overall in the 2010 Major League Baseball Draft. He signed a 4-year, $2.99 million Major League contract on August 16, 2010, meaning the Reds must have him on the active roster by the end of the 2013 season. He played his first professional ball for the Arizona League Reds in 2010. In 28 at-bats, he had eight hits and four walks. He batted .305 with 14 homers and 68 RBIs at Class A, Double-A and Triple-A in 2011, quickly rising through the farm system.
On December 17, 2011, he was traded by Cincinnati, along with Edinson Volquez, Yonder Alonso, and Brad Boxberger, to the San Diego Padres for Mat Latos. Grandal was the third catcher on the Padres' 40-man roster, joining Nick Hundley and John Baker. He started the 2012 season with the Triple-A Tucson Padres. According to MLB.com, he was the Padres' third-ranked prospect and the fifth-best catching prospect in MLB. After batting .317 with a .421 OBP and four home runs, 23 RBIs in 120 at-bats, Grandal was promoted to San Diego as they needed another batter on the bench. He made his major league debut on June 2, 2012, entering as a defensive replacement and flying out in his only at-bat. He was reassigned to Tucson the next day. He was named to appear in the 2012 All-Star Futures Game.
In his first major-league start just hours after being recalled from Tucson on June 30, 2012, Grandal became the first player in MLB history to homer from both sides of the plate for his first career hits in the same game. He was also the second Padre to have a pair of round-trippers in his first career start since Keith Lockhart achieved it in 1994, and the fourth in team history to do it from each side of the plate in a single contest. He later became the seventh player to hit three home runs for his first three hits in the majors since 1900.[a] On July 4, he hit a two-run pinch hit homer for his fourth homer in his first six hits. Grandal finished the year hitting .297/.394/.469 with 8 HR and 36 RBI in 60 games, 52 of them starts.
On November 7, 2012, MLB suspended Grandal for 50 games for testing positive for having a high testosterone level. He did not appeal the suspension and served his suspension at the beginning of the 2013 season.
In a January 2013 report, Grandal, along with several other Major League Baseball players, was linked to Biogenesis of America, a clinic that allegedly produces performance enhancing drugs. On July 6, 2013, Grandal suffered a knee injury and left the game. An MRI revealed that there was significant damage in the ACL and MCL, which prematurely ended Grandal's 2013 season. He underwent surgery to repair the torn ACL and MCL on July 9, 2013 in which Grandal could also miss the start of the 2014 season.