[14] When Mark Teixeira suffered an injury during the 2010 American League Championship Series, the Yankees replaced him on their postseason roster with Núñez.

[22] With the Yankees, Núñez played approximately two games a week, allowing Derek Jeter and Alex Rodriguez to rest more often.

[24] In addition to playing various infield positions, manager Joe Girardi also used Núñez as an outfielder when Nick Swisher experienced tendinitis in his elbow.

[27] Despite his defensive struggles, the Yankees viewed Núñez as likely to make their 25-man roster out of spring training in 2012 as a utility infielder.

The day after he committed two errors in a game against the Tampa Bay Rays, Núñez was demoted to the Triple-A Scranton/Wilkes-Barre team.

[30][31][32] On September 1, 2012, the Yankees promoted Núñez from Triple-A and manager Joe Girardi placed him into the starting lineup against the Baltimore Orioles for that day.

[35] In Game 3 of the 2012 ALCS, Núñez hit his first career postseason home run off of Tigers pitcher Justin Verlander.

Jeter began the season on the disabled list, and Núñez started at shortstop for the Yankees on Opening Day.

Núñez was placed on the 15-day disabled list on May 12 after missing the previous week due to soreness in his left rib cage.

[38] In spring training in 2014, Núñez competed with Zelous Wheeler, Yangervis Solarte, Dean Anna, and Scott Sizemore for a reserve infielder role with the Yankees.

[39] With reserve infielder Brendan Ryan starting the season on the disabled list, the Yankees chose Anna and Solarte over Núñez.

[42] With the hope of improving their offense,[38] the Minnesota Twins acquired Núñez from the Yankees on April 7, 2014, in exchange for minor league pitcher Miguel Sulbaran.

[44] After batting 7-for-22 (.318) for Rochester, he was promoted to the Twins as the 26th man on their roster for a doubleheader on April 17,[45] and was optioned back the next day.

[47] On the Twins Opening Day roster in 2016, Núñez impressed in April, hitting .373 in 18 games in a reserve role.

On July 28, 2016, the Twins traded Núñez to the San Francisco Giants for left-handed minor league pitcher Adalberto Mejía.

Overall in 2016, combined with both teams, Núñez played 141 total games with a .288 batting average, 40 stolen bases, 16 home runs, and 67 RBI.

On July 25, 2017, the Giants traded Núñez to the Boston Red Sox for minor league pitchers Shaun Anderson and Gregory Santos.

[52] In finishing the 2017 regular season with the Red Sox, Núñez played 38 games with a .321 batting average and eight home runs.

[54] For both teams combined in 2017, Núñez played 114 regular season games with a .313 batting average, 12 home runs, and 58 RBIs.

[58] During the regular season, Núñez appeared in 127 games—including 70 starts at second base primarily due to Dustin Pedroia being on the disabled list—batting .265/.289/.388 with 10 home runs and 44 RBIs.

[62] Núñez was the Opening Day starting second baseman for the 2019 Red Sox,[63] as Dustin Pedroia began the season on the injured list.

On April 5, Núñez made his major league pitching debut, allowing one run in an inning of relief during a 15–8 loss to the Arizona Diamondbacks.

On April 6, 2021, Núñez signed with the Fubon Guardians of Taiwan's Chinese Professional Baseball League (CPBL).