Byrnes has been San Diego's senior vice president of baseball operations since December 2010. Byrnes takes over for Jed Hoyer, who took over as GM of the Cubs last week.
"Josh is one of the most respected and credentialed baseball executives in the game," Padres vice chairman/chief executive officer Jeff Moorad said. "His proven record and extensive background in scouting and player development make a great fit for continuing the same focus that we've had for two years.
"Thanks to Jed Hoyer's leadership, we are in a far better position to win consistently in the future than we were two years ago. We thank Jed for the lasting impact he made on the Padres. We are fortunate to have the bench strength in Josh to have a seamless transition moving forward."
Byrnes started his front office career in 1994 with Cleveland, and was named the Indians' director of scouting in 1998. The following year, he joined Colorado as assistant general manager and held that position until being named Boston's assistant GM following the 2002 season. Byrnes was named Arizona's GM in 2005.