The Twins promoted Berríos to make his major league debut on April 27, 2016. In 18 innings pitched for Rochester prior to his promotion, he was 2–0 with a 1.06 ERA and 20 strikeouts. He was recalled and optioned multiple times during the season. In 14 starts for Minnesota, he was 3–7 with an 8.02 ERA, and in 17 starts for Rochester, he was 10–5 with a 2.51 ERA.
2017
Berríos began 2017 with Rochester. After going 3–0 with a 1.13 ERA in six starts there, he was promoted to the Twins on May 13, where he spent the remainder of the season. In 26 games with Minnesota, he was 14–8 with a 3.89 ERA.
2018: All-Star season
Berríos began 2018 in Minnesota's starting rotation and made his first start of the 2018 season on April 1, 2018. He pitched a complete game three-hit shutout against the Baltimore Orioles, with 6 strikeouts, leading the Twins to a 7–0 win. Berrios tied his career high 11 strikeouts on April 12, 2018 in a 4–0 win over the Chicago White Sox. On April 18, 2018 Berríos finished with five strikeouts and no walks in seven scoreless innings for Minnesota in a game played in his native Puerto Rico before a sold-out crowd at the Hiram Bithorn Stadium. Berrios became only the second Puerto Rican pitcher to start a regular-season MLB game at Hiram Bithorn; the first being Javier Vazquez, who made four starts there in 2003 with the Montreal Expos. His second career complete game came on June 7th against the Chicago White Sox, he became the 9th Twins pitcher to pitch a complete game and strikeout at least 10 batters without allowing a walk. Owning an 8–7 record with a 3.54 ERA over 18 starts, Berríos was named to the 2018 MLB All-Star Game. He was the only Twin selected to participate in the all-star game. In the All-Star Game, Berríos pitched one scoreless 5th inning, earning a hold in the game. Berríos finished the season with 12–11 record with a 3.84 ERA and 202 strikeouts over 32 starts, leading the league in complete games and complete game shutouts.
2019
On March 5, 2019, it was reported that Berrios would start opening day against the Cleveland Indians. He went 7.2 innings and had 10 strikeouts while not allowing a run. He received the win and the Minnesota Twins won 2–0. On July 3, 2019, it was announced that Berríos would participate in the 2019 MLB All-Star Game.
Berríos is married to Jannieliz Márquez. They have three children: Valentina, Sebastián, and Diego. Berríos' wife Jannieliz is the sister of Irmarie Márquez, who is married to Javier Báez, an infielder for the Chicago Cubs.
Philanthropy
During the offseason, Berríos went to his hometown of Bayamón and delivered water, food, and other supplies to people in need as a consequence of Hurricane Maria which caused massive damage to Puerto Rico in September 2017.