Byrnes was dismissed as general manager of the D-backs on July 2. Byrnes follows A.J. Hinch to San Diego.
Hinch, the former manager of the D-backs, was hired in September by the Padres as vice president in charge of professional scouting.
"I'm excited to work with Josh again," said Padres general manager Jed Hoyer, who had previously worked with Byrnes in Boston. "He's one of the best baseball minds in the game and will be a terrific addition to our front office."
Byrnes interviewed for the Mets' vacant general manager opening last month that went to former Padres president Sandy Alderson.
Byrnes was dismissed from his post in Arizona after the D-backs got off to a 31-48 start. Byrnes, who was hired by Jeff Moorad in Arizona in 2005 at the age of 35, was given an eight-year extension in 2008.
Moorad is now the vice chairman and CEO of the Padres.
The 2011 season will mark Byrnes' 18th season in Major League Baseball. He started his career in the front office with the Indians in 1994 and was named director of scouting in Cleveland in 1998.
Byrnes joined the Rockies as assistant general manager in 1999 before moving to Boston to serve as the assistant general manager there starting in 2003. He worked there until he was named general manager of the D-backs in November 2005.