The Twins assigned Kepler to the Rochester Red Wings of the Class AAA International League to start the 2016 season. After playing in two games for Rochester, the Twins promoted him to the major leagues to replace the injured Danny Santana on April 10, 2016. Fifteen days later, Kepler was optioned to Rochester. On June 1, 2016 Kepler was recalled to replace the injured Miguel Sanó, and he began getting regular starts for the Twins in right field. The next day, Kepler had his first multi-hit game, and on June 12, Kepler swatted his first major league home run, a walk-off three-run shot in the 10th inning off of Matt Barnes of the Boston Red Sox. On August 1 against the Cleveland Indians, Kepler became the first European-born MLB player to hit three home runs in one game and the 5th Twins player to do so after Bob Allison, Harmon Killebrew, Tony Oliva and Justin Morneau. On August 8, 2016 Kepler was named co-American League Player of the Week, his first time receiving that honor, alongside teammate Joe Mauer.