Mesoraco was born on June 19, 1988, in Punxsutawney, Pennsylvania, the son of Laura and Doug Mesoraco. He resides in Lakeland, Florida.
Mesoraco attended Punxsutawney Area High School in Punxsutawney, Pennsylvania, where he was a catcher for the Chucks baseball team. He set school records in walks, runs, hits, doubles, home runs and stolen bases. He was named the 2007 Pennsylvania Gatorade Player of the Year. In that same year, he helped the Chucks win the PIAA Class AAA State Championship played at Peoples Natural Gas Field, home of the Altoona Curve.
He got married to his longtime fiancée, Kira, On November 15, 2014, at St. Cosmas & Damian church in Punxsutawney.
Mesoraco was drafted by the Cincinnati Reds with the 15th overall pick of the 2007 Major League Baseball Draft. Mesoraco is widely known by Reds fans as "The Groundhog" from Punxsutawney. He is only the third catcher taken by the Reds with their first pick. He played 40 games for the rookie-class Gulf Coast League Reds, hitting .219 in 137 at-bats.
He spent 2008 with the single-A Dayton Dragons. Mesoraco hit .261 with nine homers and 42 RBI in 306 at-bats. He hit a grand slam on July 10 and had a two-homer game on July 21. He also had a four-hit game on August 15.
Mesoraco was invited to big league camp in 2009. However, 2009 was a low point in his career statistically. He hit .228 with eight homers and 37 RBI in 312 at-bats for the single-A advanced Sarasota Reds.
Mesoraco started 2010 with the single-A advanced Lynchburg Hillcats. He hit .355 in 43 games before being promoted to double-A Carolina. He hit .294 in 56 games for the Mudcats, and was again promoted, this time to the triple-A Louisville Bats. He was 12-for-52 in 14 games for the Bats. Mesoraco finished the season with a combined 25 doubles, 26 home runs, and 75 RBI. He earned a trip to the Arizona Fall League, where he hit .242 with two homers and 11 RBI.
Many thought Mesoraco would be added to the 40-man roster following the 2010 season, but the Reds re-signed Ramón Hernández, and Mesoraco was left off.
Prior to the 2012 season, Mesoraco was ranked as the top prospect in the Reds organization according to Baseball America. That same year, he was also ranked by Jonathan Mayo of MLB.com as the 14th best prospect in baseball.
He was added to the 40-man roster, played in the 2011 Futures Game, and called up as a September call-up for the Reds in 2011.
Mesoraco made his Major League debut on September 3, 2011. He appeared in 18 games for the rest of 2011 with a .180 batting average, 2 homers, and 6 RBI.
On July 30, 2012, Mesoraco was ejected from a game against the San Diego Padres for arguing with umpire Chad Fairchild. Mesoraco then proceeded to bump the umpire. He would return to the lineup the next night but left during the game due to dizziness from being overheated. He was placed on the 7-day disabled list due to a concussion the next day. Mesoraco also received a three-game suspension, which was reduced to two games upon appeal. He played in 54 games of 2012 batting .212 with 5 home runs and 14 RBI.
In 2013, Mesoraco gained a little more playing time as he played in 103 games batting .238 with 9 home runs and 42 RBI.
Landing on the disabled list twice in the early part of the 2014 season, as of June 4 Mesoraco was batting .294 but had yet to amass a sufficient number of at-bats to be listed among Major League Baseball's leaders in the category. Mesoraco was named to play for the NL in the 2014 MLB All-Star Game. He finished the season with 25 home runs and 80 RBI in 114 games, leading all major league catchers in home runs and slugging percentage.
On January 26, 2015 The Cincinnati Reds and Mesoraco agreed to a four-year contract extension worth $28 million. Later on June 20, 2015, Mesoraco announced that he would undergo left hip surgery, causing him to miss the rest of the 2015 season. Limited to 23 games in 2015, Mesoraco batted .275 with 2 RBI.
Mesoraco again had a short-lived season in 2016 as he played only 16 games with 1 RBI on a .140 average. On May 6, 2016, Mesoraco opted to have surgery on his left shoulder that was diagnosed with a torn labrum, causing Mesoraco to miss the rest of the 2016 season.