Donovan played 45 minutes in Friday's 2-0 win over Jamaica but was not on the roster for Tuesday's game against Panama.
"Landon is still struggling with the ankle injury from a couple weeks ago, so he will go back to Los Angeles and try to get back to 100 percent," said U.S. Coach Jurgen Klinsmann.
Donovan is one of four U.S. team members who will not be on the field Tuesday.
Matt Beslet and goalkeeper Tim Howard were taken off the roster as part of a planned player rotation, and Jermaine Jones was scratched due to a knee injury.
"Jermaine's case is more of a concern," Klinsmann said in a written statement. "It's clear that the issue with his knee is something that should be taken care of right away so he can be 100 percent."
Howard's departure means Aston Villa's Brad Guzan will start against Panama. Chicago Fire keeper Sean Johnson took Howard's slot on the roster.