They will also end nonstop flights from New York's LaGuardia Airport to Atlanta, Cleveland and Minneapolis but will add service from LaGuardia to 10 other cities.
The combined company, American Airlines Group Inc., announced the changes Wednesday.
American and US Airways agreed in November to give up the space at Reagan and LaGuardia and a few gates at five other major airports. In exchange, the U.S. Justice Department dropped an antitrust lawsuit that threatened to derail their merger, which created the world's biggest airline operator.
Slots at Reagan and New York-area airports are limited, making them valuable when they become available. Southwest Airlines and Virgin America won the rights to buy the LaGuardia slots. An announcement is expected soon on who will get the Reagan slots and what cities they'll serve with them.
American and US Airways will remain major carriers at Reagan and LaGuardia.
Henry Harteveldt, a travel-industry analyst for consulting firm Hudson Crossing, noted that American is pulling out of several nonstop routes also flown by rival Delta Air Lines Inc., including Reagan to Atlanta, Detroit and Minneapolis and LaGuardia to Atlanta. At the same time, American will add a second daily nonstop between Washington and Los Angeles, and start new service to New York from secondary markets.
"This is American creating a truce with Delta," he said. "It's a smart move ... where you're not as strong, move your assets."
American's chief marketing officer, Andrew Nocella, said the changes were designed to minimize the effect of slot losses on service to smaller cities. He said the new combined airline "will fly more customers to more places than ever before."
Besides Detroit and San Diego, daily nonstops by American and US Airways will end between Reagan and Minneapolis; Montreal; Augusta and Savannah, Ga.; Fayetteville and Jacksonville, N.C.; Fort Walton Beach, Pensacola and Tallahassee, Fla.; Islip, N.Y.; Little Rock, Ark.; Myrtle Beach, S.C.; Nassau, Bahamas; and Omaha, Neb. It will switch from year-round to only seasonal flying to Fort Myers, Fla.
The company said dates for the changes would be announced in coming weeks. Travelers in those cities will have to fly through another American or US Airways hub city - or take another airline -to reach Washington.
Service will be added beginning April 1 between LaGuardia and Charlottesville, Norfolk, Richmond and Roanoke, Va.; Little Rock; Dayton, Ohio; Louisville, Ky.; Greensboro and Wilmington, N.C.; and Knoxville, Tenn.
Shares of American Airlines Group Inc. fell 3 cents to close at $28.84.