The team announced the dismissal in a release Sunday, just minutes before the Padres were to face the Los Angeles Dodgers.
Padres president and CEO Mike Dee said in the statement the team will begin a search for a new GM immediately. In the interim, senior vice president for baseball operations Omar Minaya and assistant general managers AJ Hinch and Fred Uhlman, Jr. will share Byrnes' role.
Minaya was the general manager of the New York Mets from 2005-10.
"This ownership group is committed to fielding a team that consistently competes for postseason play," Dee said. "Thus far this season, the results on the field have been mixed at best and clearly have not lived up to expectations. After a lengthy evaluation of every facet of our baseball operations, we have decided to make this change today."
Byrnes was hired by the Padres as their senior vice president for baseball operations in December 2010 after he was let go as general manager of the Arizona Diamondbacks, where he was in the middle of an eight-year deal. He was promoted 10 months later to GM and was given a five-year contract.
Under Byrnes, the Padres payroll increased nearly $40 million to $89,881,696 on Opening Day this season -- 23rd overall -- but the team has made little progress.
After finishing with 76-86 records in his first two seasons, the Padres are 32-43 and 12½ games back in the NL West during an injury-plagued season.
Byrnes was touted by the Padres as excelling at scouting and player development, but his biggest moves came through trades. He sent first-base prospect Anthony Rizzo to the Cubs for top-line starter Andrew Cashner, and he dealt starting pitcher Mat Latos for infielder Yasmani Grandal, catcher Yonder Alonso, and right-handers Edinson Volquez and Brad Boxberger.
Byrnes also acquired starter Tyson Ross, right-hander Joaquin Benoit, closer Huston Street, outfielder Carlos Quentin and right-hander Ian Kennedy.
Struggling Padres Fire GM Byrnes
ESPN.com MLB writer Christina Kahrl discusses the Padres' decision to fire GM Josh Byrnes and the future of manager Bud Black.