Severino ended the season having thrown a career-high 193 ⁄3 innings in 31 starts, with a 14–6 record, 2.98 ERA, 1.04 WHIP, .208 opponent batting average, 5.3 bWAR, 5.7 fWAR and 230 strikeouts, tied with CC Sabathia for the third-most single-season strikeouts in Yankees history, and the most strikeouts in a single season by a right-handed pitcher in Yankees history in the Modern Era (post 1920). He also became the first Yankee starter to qualify for the ERA title with a sub-3.00 ERA since David Cone and Andy Pettitte both did so in 1997 and the youngest Yankee starter to do so since Dave Righetti in 1981. His 16 starts of one run allowed or less led the major leagues, additionally he was the first Yankee starter to have 16 starts with one or no runs allowed in a single season since Mike Mussina in 2001 and the youngest pitcher in the major leagues to reach this mark since Dwight Gooden in 1985. He also became the first American League pitcher with an ERA below 3.00 and 230 or more strikeouts in their age-23 season or younger since Roger Clemens in 1986. He led all major league pitchers with an average fastball velocity of 97.6 miles per hour.

Severino signed with the New York Yankees as an international free agent on December 26, 2011, agreeing on a $225,000 signing bonus. He had agreed to terms to sign with the Colorado Rockies, but a Yankees scout matched their offer and convinced Severino to play for the team he had grown up as a fan of. At the time, he could throw his fastball at 91 miles per hour (146 km/h). He made his professional debut for the Dominican Summer League (DSL) Yankees 1 that year. He started 14 games, pitching to a 4–2 win-loss record with a 1.68 earned run average (ERA) and 45 strikeouts in 64 ⁄3 innings. He started 2013 with the DSL Yankees 1 and was promoted to the Charleston RiverDogs of the Class A South Atlantic League during the season. He finished 4–2 with a 2.45 ERA, 53 strikeouts over 44 innings in 10 games (eight starts). His fastball velocity reached 97 miles per hour (156 km/h) at Charleston.

Prior to the 2014 season, Baseball America ranked him as the Yankees ninth-best prospect. Severino started the season with Charleston before being promoted to the Tampa Yankees of the Class A-Advanced Florida State League. After his promotion to Tampa, he was selected to appear in the 2014 All-Star Futures Game in July. After the Futures Game, he was again promoted, to the Trenton Thunder of the Class AA Eastern League. Combined between the three teams, Severino went 6–5 win-loss record with a 2.46 ERA, 127 strikeouts, and 27 walks in 24 games (all starts) and 113 innings pitched. Before the start of the 2015 season, Severino was ranked the best prospect in the Yankees farm system and the 23rd best out of all minor league players by MLB Pipeline. He was ranked 35th by Baseball America.

With a late-July injury to Michael Pineda, and the Yankees not acquiring a starting pitcher before the trade deadline, Brian Cashman, the general manager of the Yankees, announced that Severino’s next start would come in the major leagues against the Boston Red Sox, the primary rival of the Yankees, at Yankee Stadium. Though Severino set a career-high with 113 innings pitched in the 2014 season, Cashman said that Severino would not be limited in how many innings he throws over the remainder of the 2015 season, in part because they limited his innings earlier in the season.

Yankees’ manager Joe Girardi set Severino’s major league debut for August 5. Severino pitched five innings in his debut, allowing two hits, two runs (one earned), with seven strikeouts and no walks. At age 21, he was the youngest pitcher to make a start in the 2015 MLB season. Additionally, he became the first AL pitcher in MLB history to strike out seven hitters while walking none and allowing no more than two hits in their major league debut. He ended his rookie season having started 11 games, pitching 62 ⁄3 innings with a 5–3 record, 2.89 ERA and 56 strikeouts.

Severino is from Sabana de la Mar, in the Hato Mayor province of the Dominican Republic. He grew up a fan of the Yankees, particularly fellow Dominican Robinson Canó. Severino and his wife, Rosmaly, have one daughter, who was born in July 2015.

Severino began the 2016 season in the Yankees starting rotation. In a game against the Chicago White Sox on May 13, 2016, Severino left the game with an apparent injury after giving up 7 runs in 2.2 innings. The next day, he was placed on the 15-day disabled list due to right triceps inflammation. On May 30, 2016, he was activated from the disabled list, and optioned to the Triple-A Scranton/Wilkes-Barre RailRiders. He was called back up on July 25 and was primarily used as a reliever for the remainder of the season. On September 26, Severino was ejected for the first time in his Major League career after hitting Justin Smoak with a pitch. This followed after he hit Josh Donaldson on the elbow and Blue Jays starter J.A. Happ hit Chase Headley with a pitch in the first inning.

Following Spring Training, Severino was named the Yankees fourth starter. On April 13, 2017, Severino struck out a career-high 11 batters in seven innings as the Yankees won 3–2 over the Tampa Bay Rays. In his following start, Severino struck out 10 batters in a career-high eight innings in a 4–1 loss to the Chicago White Sox. On April 26, Severino pitched seven shutout innings against the Boston Red Sox. On May 24, Severino pitched eight shutout innings against the Kansas City Royals. As of June 10, he had a 5–2 record with a 2.75 ERA. In a no-decision, he struck out a career-high 12 batters in seven innings against the White Sox on June 27 as the bullpen blew a lead for the sixth time in Severino’s starts. Despite his strong start, Severino struggled to end the first half, allowing 16 earned runs in four starts from June 15 to July 2, for a 7.03 ERA in that span. He finished his first half on a high note though, striking out 10 batters over seven innings of three-run ball against the Milwaukee Brewers on July 8, his fourth start of the season with at least 10 strikeouts. Severino was named to the American League All-Star team alongside his teammates Aaron Judge, Gary Sanchez, Starlin Castro and Dellin Betances. In the first half of the season, he had posted a 5–4 record with a 3.54 ERA and 124 strikeouts in 106⅓ innings. His 10.50 strikeout per-9 ratio ranked in the top five of the American League.

Severino started the second half strong, first matching Chris Sale by allowing one run over seven innings in a pitcher’s duel against the Red Sox. In his next start, he fired seven shutout innings against the Seattle Mariners and then allowed zero earned runs in seven innings against the Cincinnati Reds. As of July 27, Severino was tied with Max Scherzer for second-most starts (8) of at least seven innings pitched with one earned run or less in the 2017 season, behind Clayton Kershaw’s 11. On August 17, 2017, Severino collected his first Major League hit off Steven Matz against the New York Mets. He collected his 11th win holding the Detroit Tigers to one earned run over 6⅔ innings with eight strikeouts on August 23. On September 3, against the Boston Red Sox, Severino struck out his 200th batter of the season, becoming the second-youngest Yankee in franchise history with 200 strikeouts in one season behind Al Downing in 1964. In the second half of the season, he went 9–2 with a 2.28 ERA in 14 starts, allowing no more than one earned run in ten of those starts.

With a three-quarters delivery, Severino currently throws three pitches: a four-seam fastball averaging 96 mph, a slider, and a change-up. His fastball was clocked at 101 mph in 2017. His average spin rate for sliders was ranked no. 2 in the MLB (2910 rpm) behind Garrett Richards (2919 rpm) in 2018.

On March 17, 2018, the Yankees named Severino their Opening Day starter. He struck out seven and allowed one hit in 5 ⁄3 innings against the Toronto Blue Jays. On May 2, 2018, against the Houston Astros, Severino pitched a complete game for the first time in his major league career, shutting out the Astros 4–0. Severino allowed zero runs and struck out 10. From April 16 to June 4, Severino posted ten consecutive quality starts of at least six innings pitched and three earned runs or less allowed (in six of those he allowed one or no earned runs), during this time span he went 7–0 with a 1.85 ERA in 68 innings, giving up only 45 hits (4 home runs), striking out 82, walking just 14 batters, and limiting opponents to a .184 batting average. Severino earned his 10th win of the season on June 16 after limiting the Rays to three hits and two walks in eight shutout innings with nine strikeouts, double his win count prior to the All-Star break in 2017, and becoming the first Yankee pitcher to win 10 or more games prior to the All-Star break since Masahiro Tanaka in 2014. On July 1, Severino became the first Yankee since CC Sabathia in 2011 to win 13 games prior to the All-Star break after throwing 6 ⁄3 shutout innings to beat the Red Sox.

On February 15, 2019, Severino signed a four-year, $40 million contract extension that included a club option for a fifth season worth an additional $12.25 million.

On March 15, it was revealed that Severino was diagnosed with rotator cuff inflammation on his right shoulder. This put him out of action for all of April. On April 9, it was revealed that Severino was diagnosed with a Grade 2 lat strain, ruling him out for an additional six weeks. He did not play in any rehab assignments until September. He started for the Yankees on September 17, 2019 against the Los Angeles Angels in New York, and made two more starts in the regular season.

On February 25, 2020, it was announced that Severino would undergo Tommy John surgery to repair a partially torn UCL in his right elbow, ending his 2020 season. He officially underwent the surgery on February 27 along with removing a bone chip from his right elbow.