Núñez was called up to the majors for the first time on August 19, 2010 after Lance Berkman was placed on the 15-day disabled list. Núñez debuted on the same day, replacing Jeter in the seventh inning and fouling out in his only plate appearance. Núñez received playing time as a fill-in for Jeter and the then-injured Alex Rodriguez. On August 21, Núñez recorded his first major league hit, a go-ahead RBI single into right field. Núñez hit his first career home run against the Chicago White Sox on August 28, 2010. He also stole his first career base the same day. In 30 games for the Yankees, Núñez hit .280, with one home run, seven RBIs, and scored 12 runs. When Mark Teixeira suffered an injury during the 2010 American League Championship Series, the Yankees replaced him on their postseason roster with Núñez. After the season, "Baseball America" rated him as the eighth-best prospect in the Yankees organization, while also naming him the "Best Defensive Infielder" and the "Best Infield Arm" in the Yankees organization.