Five Guys also has lined up a location in Fashion Island's Atrium Court. Both locations are planned to begin serving in mid-July.
"They're areas that really fit our model really well," said Kevin Nelson, vice president of operations for Monument Restaurants, the Georgia-based franchisee that will operate the two Five Guys locations.
Five Guys is generally more expensive than In-N-Out and doesn't have drive-thrus, among other differences. But experts in the restaurant business have predicted they will compete.
As first reported in the Orange County Register, the Costa Mesa location will be in the shopping center with Target, in the space now vacant after a Baja Fresh Mexican Grill restaurant recently closed.
The In-N-Out on Harbor opened in December to much fanfare and became Costa Mesa's second restaurant of the Irvine-based chain.
In Atrium Court, Five Guys will replace a Fatburger.
"We think there's enough pie to go around in the Southern California market," Nelson said.
Monument already runs a Five Guys in Huntington Beach and plans to open one in The District shopping center in Tustin and another in Laguna Niguel.
The chain plans to eventually have more than 200 locations in Southern California. Now, there are 27 locations in the state, and a total of 770 in U.S. and Canada. It was founded in 1986 by five brothers.