On May 23, 2013, Encarnación hit his fifth career grand slam to give the Blue Jays an 8–3 lead over the Baltimore Orioles. The Jays would win the game 12–6.
On July 6, 2013, Encarnación was named to his first all-star game as a reserve designated hitter for the American League. Encarnación was one of four Blue Jays to be named, the others being José Bautista, Brett Cecil, and Steve Delabar. Up to the All-Star break, Encarnación posted a triple-slash of .264/.353/.532 with 25 home runs and 72 RBIs. In the All-Star Game, Encarnación entered as a pinch-hitter for David Ortiz in the seventh inning, and finished the game 0–2. In a game against the Houston Astros on July 26, 2013, Encarnación became only the second Blue Jay in franchise history to hit two home runs in one inning, joining Joe Carter who did so on October 3, 1993 – tying the Major League record for most home runs in an inning. Leading off the 7th inning behind at 6–4, Encarnación hit a solo home run and would later hit his sixth career grand slam, receiving a curtain call afterwards as the Blue Jays would score 8 runs in the inning and lead 12–6. He was named the American League Player of the Week on July 29, after batting .520 with three doubles, two home runs, and eight RBIs over the prior week. Encarnación hit his 30th home run of the season on August 7, 2013, against the Seattle Mariners. In doing so, he recorded back-to-back 30 home run seasons for the first time in his career. Playing against the Kansas City Royals on August 31, 2013, Encarnación recorded his 1,000th career hit, a single off Kansas City starter Jeremy Guthrie. On September 2, he reached 100 RBIs for the second consecutive season on a two-run home run against Brandon McCarthy of the Arizona Diamondbacks. He spent time on the bench in mid September with a wrist injury, but made a brief comeback before being placed on the disabled list on September 17. He underwent successful surgery on September 19. Encarnación finished the 2013 season with a .272 average, 36 home runs, and 104 RBIs. He finished with more walks than strikeouts for the first time in his career, with 82 and 62 respectively.