[8] After a solid 2006 spring training, Mathis was expected to see substantial playing time at catcher, sharing the position with José Molina.

[14] In the beginning of July, Napoli sustained a high ankle sprain, making the Angels recall Mathis to the majors.

[17] On July 21, Molina was traded to the New York Yankees, making Napoli and Mathis hold the two catcher positions for the rest of the season.

[12] On July 23, 2008, Mathis had 4 hits and 6 RBI (the highest in a single game for both categories that season) in a 11–14 win against the Cleveland Indians.

Mathis noted that his team's pitcher, John Lackey, "obviously didn't have his best stuff today, but he kept battling through it... and luckily we were able to put some runs on the board for him.

[12] In game 3 of the 2009 American League Championship Series, Mathis hit an 11th-inning walk-off RBI double, defeating the New York Yankees 5–4.

[20] In spite of his poor regular season stats (.211 batting average), he used his strong playoff offensive performance and excellent defensive skill to bolster his case for a raise to $1.3 million, beating the Angels management in arbitration.

[27] On November 19, 2012, Mathis was traded to the Miami Marlins along with Adeiny Hechavarria, Henderson Álvarez, Yunel Escobar, Jake Marisnick, Anthony DeSclafani, and Justin Nicolino, in exchange for Mark Buehrle, Josh Johnson, José Reyes, John Buck, and Emilio Bonifacio.

In his first spring training game with the Marlins on February 23, 2013, Mathis broke his collarbone on a foul tip hit by Matt Holliday.

On June 30, he hit a walk-off grand slam against Tyson Ross of the San Diego Padres to give Miami the win, 6–2.

On defense, he helped Lance Lynn and Mike Minor finish in the top 10 in AL Cy Young Award voting.

[37] On February 16, 2021, Mathis signed a minor league contract with the Philadelphia Phillies organization that included an invitation to spring training.

[40] On May 2, 2021, Mathis was selected to the active roster after starter Travis d'Arnaud and backup Alex Jackson were placed on the injured list.

After leaving the Angels, Mathis became a heavily defensive catcher who excels in pitch framing and catching base stealers.

Because of these skills, he was a preferred catcher to pitchers such as Jose Fernandez and Zack Greinke, despite being among the league worst in many batting statistics.