After a two-week tryout, the Yankees signed Nova as an international free agent on July 15, 2004. Nova received an $80,000 signing bonus, about the average bonus given to a Dominican prospect. Though other teams would have offered Nova more money, he insisted on signing with the Yankees.

Nova made his professional debut with the Gulf Coast Yankees in the Rookie-level Gulf Coast League in 2006, where he accumulated a 3–0 win–loss record with a 2.72 earned run average (ERA). After starting the 2007 season in extended spring training, the Yankees assigned him to the Charleston RiverDogs of the Class A South Atlantic League.

In 2008, Nova pitched for the Tampa Yankees of the Class A-Advanced Florida State League. Nova started the season with an 0–5 win–loss record and a 5.06 ERA, at which point he considered quitting baseball. But Nova persevered, and he rebounded to finish the season with an 8–13 win–loss record and a 4.36 ERA in 26 games, 24 of which he started. He recorded 109 strikeouts and 46 walks.

The Yankees opted not to add Nova to their 40-man roster after the 2008 season, exposing him to the Rule 5 draft that off-season. They calculated that Nova, if selected, would be returned to the organization by the end of spring training, as he was unlikely to last the entire season on a team’s 25-man roster, as required by the Rule 5 process. In December 2008, the San Diego Padres selected Nova with the twentieth selection in the Rule 5 draft. Competing for a spot on the Padres’ roster, Nova had an 8.31 ERA in spring training, allowing eight earned runs and 13 hits in 8 ⁄3 innings pitched, while walking four and striking out three. He was returned to the Yankees after clearing outright waivers at the end of spring training.

After recording a 2.43 ERA and 1.27 walks plus hits per inning pitched (WHIP) ratio over his first six starts for Scranton/Wilkes Barre, Nova was promoted to the major leagues on May 10, 2010, to serve as a long reliever in the Yankees’ bullpen. He pitched three shutout innings in relief before he was optioned back to Scranton/Wilkes-Barre. Nova was recalled to the majors on August 21, and he made his first career major league start on August 23. He impressed the Yankees in his first start, going 5 ⁄3 innings and allowing two runs on six hits against the Toronto Blue Jays. He was given his second start, replacing Javier Vázquez in the Yankees’ starting rotation. Nova struck out seven Chicago White Sox in his first MLB victory on August 29.

At the time of his MLB debut, the league investigated Nova and fellow Yankees pitching prospect Wilkins de la Rosa for injecting each other with Vitamin B12. Overall, Nova made seven starts for the Yankees in 2010, pitching to a 1–2 record and a 4.50 ERA. Nova reached the sixth inning only once, however, as he allowed a higher opponents’ batting average and ERA in the fifth inning than in the first four. The Yankees did not include Nova on their postseason roster.

Nova’s family resides in the Dominican Republic. His father traveled to the United States to watch his second MLB start in person. Nova dedicated his 2011 season to his grandfather, who died in 2010.

Nova entered spring training in 2011 expected to secure a spot in the starting rotation. Nova was named to the Yankees’ starting rotation. On June 20, Nova had the longest start in his career (at that time), allowing one run in eight innings against the Cincinnati Reds, while striking out seven. Through June, Nova had an 8–4 win–loss record and 4.15 ERA, including a 4–1 record and 3.35 ERA in his six most recent starts.

Nova compiled a 16–4 record in 2011, the most wins for a Yankees rookie since Stan Bahnsen won 17 games in 1968. He also had a 3.70 ERA. He was named to the Baseball America All-Rookie Team following the season. Nova finished fourth in balloting for the American League (AL) Rookie of the Year Award, finishing behind Jeremy Hellickson, Mark Trumbo, and Eric Hosmer.

Nova worked in 2011 to develop his slider, changing his grip at the suggestion of Yankees executive Billy Connors. The work paid off, as his slider garnered a whiff rate of 43% in 2011. Nova’s changeup is not his main weapon and is not used against right-handed hitters.

Nova struggled at the beginning of the 2012 season, recording a 5.60 ERA through May, but decreased it to 3.92 by the All-Star break. During an interleague game against the Atlanta Braves on June 11, 2012, Nova got his first career base hit off of Randall Delgado in a 3–0 win. Nova was not very effective after the All-Star break, pitching to a 2–5 record with a 6.40 ERA in 10 starts, and was placed on the 15-day disabled list due to rotator cuff inflammation. Due to his struggles late in the season, the Yankees decided to demote Nova to the bullpen for the postseason roster until the team lost in the 2012 ALCS to the Detroit Tigers. Despite his 5.02 ERA, he still finished the 2012 season with a record of 12–8 in 28 starts.

Nova struggled in his first four starts of the 2013 season, in which he failed to pitch past the fifth inning, pitching to a 1–1 record and a 6.28 ERA. On April 27, 2013, Nova was placed on the 15-day disabled list after an MRI revealed he had inflammation of his right triceps. Nova was activated on May 24, 2013, and demoted to the bullpen. He pitched an immaculate inning on May 29, 2013 against the New York Mets. However, he was demoted to Scranton/Wilkes-Barre the next day, as the Yankees decided they wanted Nova to continue to start.

Nova began a throwing program to rehabilitate his arm in September, and spent the winter at the Yankees’ spring training facility in Tampa, Florida, rather than returning to the Dominican Republic. The Yankees signed Nova to a $3.3 million contract for the 2015 season, avoiding arbitration. On April 11, 2015, the Yankees placed Nova on the 60-day disabled list to begin the season recovering from his Tommy John surgery. He made his first rehabilitation start on June 8, and returned to the Yankees on June 24. Nova pitched to a 5.11 ERA in 14 starts before the Yankees took him out of the starting rotation on September 16; however, Nova returned to the rotation due to an injury to Masahiro Tanaka. He finished the 2015 season with a 6–11 record and a 5.07 ERA.

On August 1, 2016, the Yankees traded Nova to the Pittsburgh Pirates for two players to be named later. On August 30, the players were identified as Stephen Tarpley and Tito Polo. Nova made 11 starts for the Pirates, and pitched to a 3.06 ERA with 52 strikeouts and three walks in 64 ⁄3 innings pitched. He also pitched three complete games.

On December 27, 2016, Nova officially signed a three-year, $26 million contract with the Pirates. Nova won the National League’s Pitcher of the Month Award for April 2017, after he led the league with an 0.75 WHIP, was second with 36 innings pitched and a 1.50 ERA, and threw two complete games (one shutout). After throwing six shutout innings against the Miami Marlins on June 11, Nova became the first Pirate to throw at least six innings in his first thirteen starts to begin a season since Eddie Solomon in 1981, who did it seventeen times. Nova’s streak ended at fifteen starts, after pitching five innings of two run ball in a 6–2 win over the Rays in his sixteenth start of the year. At the All-Star break, Nova had a 3.21 ERA in 120 ⁄3 innings across 18 games started. He struggled in the second half of the season, including a three inning outing on August 30, which led the Pirates to skip Nova’s next start. He ended the season with a 4.14 ERA in 187 innings pitched.

Nova started for the Pirates on Opening Day in 2018. He finished the season with a 9–9 record, a 4.19 ERA, 114 strikeouts and 35 walks in 161 innings pitched. He had the lowest fielding percentage among major league pitchers, at .792, and the most errors, with five.

On December 11, 2018, the Pirates traded Nova to the Chicago White Sox for Yordi Rosario and $500,000 of international signing bonus money. In 2019, Nova posted a 11–12 record with a 4.72 ERA and led the American League with 225 hits allowed. Batters hit .300 against him, the highest batting average in the major leagues.

On January 13, 2020, the Detroit Tigers signed Nova to a one-year, $1.5 million contract. With the 2020 Detroit Tigers, Nova appeared in 4 games, compiling a 1-1 record with 8.53 ERA and 9 strikeouts in 19.0 innings pitched.