On February 13, 2014, Karns was traded to the Tampa Bay Rays in exchange for José Lobatón, Felipe Rivero and Drew Vettleson.
Karns spent the majority of the season in the Rays' AAA system.
He finished the season appearing in 2 starts only.

Due to numerous injuries to begin the 2015 season, the Rays gave Karns a rotation spot for opening day.
On July 21, 2015 pitching against the Philadelphia Phillies in Philadelphia, Karns hit his first Major League home run as Rays defeated the Phillies, 1–0.
 It was the first time since 1962 that an American League pitcher had homered in a 1-0 game.
Karns appeared in 26 starts for the Rays, averaging nine strikeouts per nine innings despite just logging under 6 innings per start.
On February 13, 2014, Karns was traded to the Tampa Bay Rays in exchange for José Lobatón, Felipe Rivero and Drew Vettleson. Karns spent the majority of the season in the Rays' AAA system. He finished the season appearing in 2 starts only.
Due to numerous injuries to begin the 2015 season, the Rays gave Karns a rotation spot for opening day. On July 21, 2015 pitching against the Philadelphia Phillies in Philadelphia, Karns hit his first Major League home run as Rays defeated the Phillies, 1–0.  It was the first time since 1962 that an American League pitcher had homered in a 1-0 game. Karns appeared in 26 starts for the Rays, averaging nine strikeouts per nine innings despite just logging under 6 innings per start.
Nate Karns