Cervelli played in the Dominican Summer League in 2003. Initially a switch hitter, the Yankees had Cervelli focus on right-handed hitting.

After struggling to adjust to professional baseball in 2004 and 2005, Cervelli batted .309 for the Staten Island Yankees of the Class A-Short Season New York–Penn League in 2006. In 2007, he played for the Tampa Yankees of the Class A-Advanced Florida State League, where he batted .279 with an on-base percentage of .387 and two home runs. Baseball America rated him the Yankees’ 23rd-best prospect prior for the 2008 season.

On March 8, 2008, Cervelli fractured his wrist on a controversial play during a spring training game against the Tampa Bay Rays, when Rays infielder Elliot Johnson collided with him at home plate in the ninth inning. Joe Girardi, the Yankees manager said, “I think it was uncalled for, it’s spring training and you are going to get people hurt and we got Cervelli hurt.” He did not return to action until June.

Following the completion of the 2008 minor league season, Cervelli was called up to the Yankees. He made his major league debut on September 18, 2008, as a defensive replacement. He batted 0-for-5 in his brief time in the majors.

After starting the 2009 season in the minors, Cervelli was called up by the Yankees on May 5, 2009, when Jorge Posada was placed on the 15-day disabled list, though he was batting only .190, with a .266 on-base percentage and .310 slugging percentage at Trenton at the time of the call-up, and had not played in Class AAA. He made his first major league start on May 7, after José Molina injured his quad. He recorded his first major league hit, a single, on May 8, against the Baltimore Orioles, while also catching starting pitcher CC Sabathia during a complete game shutout. Cervelli asserted himself as a reliable defensive catcher for the New York Yankees, and received praise from his teammates. Though Cervelli was sent to the Scranton/Wilkes-Barre Yankees of the Class AAA International League on July 8, 2009. when Molina was activated off of the disabled list, Yankees’ manager Joe Girardi made clear that he was impressed with Cervelli’s performance.

On June 24, 2009, Cervelli hit his first major league home run against Kris Medlen of the Atlanta Braves, breaking up a no-hitter. On September 16, Cervelli had his first walk-off hit – a single in the bottom of the ninth inning against the Toronto Blue Jays. Cervelli was a member of the Yankees roster in the 2009 MLB postseason, as the Yankees won the 2009 World Series, but he was not on the World Series roster.

Cervelli played for the Italy national baseball team in the 2009 World Baseball Classic and the 2017 World Baseball Classic.

In 2011, Cervelli entered spring training as the backup to Russell Martin. Cervelli broke his foot in early March, and missed the beginning of the 2011 season. On April 29, 2011, the New York Yankees activated Cervelli from the disabled list, and on May 8, he hit his first home run of the season, also the first grand slam of his career, in a series tiebreaker on the road against Texas.

When Martin signed with the Pittsburgh Pirates, Cervelli became the starting catcher for the Yankees in 2013. In a game against the Blue Jays on April 26, Cervelli suffered a fractured right hand after getting hit by a foul tip by outfielder Rajai Davis; he then underwent surgery the next day and was placed on the 60-day disabled list. On August 5, 2013, Cervelli was suspended for 50 games after being linked with the Biogenesis scandal.

Cervelli competed with John Ryan Murphy and Austin Romine to be the backup catcher for the Yankees in spring training in 2014. Cervelli won the job, but suffered a hamstring injury on April 13, and was placed on the 60-day disabled list. He returned to the Yankees on June 17. On September 6, Cervelli suffered from cluster migraines. Though they were determined to not be the result of his prior concussions, he missed time while he recuperated. Cervelli finished the 2014 season with a .301 batting average in 49 games.

On November 12, 2014, the Yankees traded Cervelli to the Pirates in exchange for pitcher Justin Wilson. Cervelli started 124 games for the Pirates in 2015, in which he batted .295 and was worth 3.8 Wins Above Replacement. Runners stole a major-league-leading 101 bases against him.

Prior to the 2016 season, the Pirates signed Cervelli to a one-year contract worth $3.5 million. During the 2016 season, the Pirates signed Cervelli to a three-year contract extension, worth $31 million. In 2016 his batting dropped to .264/.377/.322 (his lowest slugging percentage of his career), as he hit only one home run in 393 plate appearances, and caught 19% of attempted basestealers.

In 2017 he batted .249 (his lowest batting average of his career)/.342/.370, as he caught 20% of attempted basestealers. On June 22, 2018, he was placed on the seven day disabled list with a concussion. He was activated a couple of weeks later but fell back to the seven day disabled list with a recurrence of the concussion symptom. In 2018 he batted .259/.378/.431 with a career-high 12 home runs.

During the crisis in Venezuela, Cervelli’s parents moved to Colombia, and his grandparents returned to Italy. Cervelli took to social media in 2017 to voice his opposition to Nicolás Maduro. He teamed with Hernán Pérez in an ongoing effort to call American attention to the issue, using techniques such as writing “SOS Venezuela” on his eye black. He led teammates in wearing “Freedom for Venezuela” t-shirts in 2019.

Cervelli suffered his sixth concussion on May 25, 2019. While rehabilitating, he decided to give up catching. He later backtracked, saying he wanted to continue catching. With the Pirates in 2019, he batted .193/.279/.248 in 34 games.

On August 22, 2019, the Pirates released Cervelli in order to give him the opportunity to receive playing time with another team. He signed with the Atlanta Braves on August 24. In his debut with the Braves, Cervelli went four for five with three doubles and three RBIs during the Braves 9-5 win over the Mets on August 24. He batted .281 with two home runs and seven RBIs in 14 games.

On January 9, 2020, Cervelli signed a one-year, $2 million contract with the Miami Marlins, to serve as a backup catcher to Jorge Alfaro. Alfaro began the season on the injured list, and Cervelli started for the Marlins on Opening Day. On August 22, 2020, Cervelli was placed on the injured list and later ruled out for the season after his seventh MLB concussion. He played in 16 games total in 2020, and announced his retirement after the regular season.