The Americans will face the squad from the Communist island nation at Audi Field, home of Major League Soccer's DC United, in the opening game of Group A play in the new CONCACAF (North American) Nations League.
Rankings for the final 2022 World Cup qualifying round will be decided after the event, so Nations League matches will help boost teams ahead of that competition.
The United States are currently ranked 24th in the world, and second in CONCACAF, behind Mexico.
Cuba are 174th, out of 211 FIFA nations, and 22nd in the region. They beat the Turks and Caicos, Grenada and the Dominican Republic in a brief qualifying tournament to make it into the top level of the Nations League where they were drawn with the USA and Canada.
The Americans are 10-1-1 against Cuba in a rivalry dating to 1947 and have won 10 in a row against the Caribbean Lions over the past 70 years, though the teams did not meet for almost 50 years after 1949, in part because the USA severed relations in 1961.
The Americans visit Toronto to face Canada four days after hosting Cuba. The US team will host Canada and visit Cuba in November to determine a semi-finalist for next June's knockout stages.
"We're excited to be competing in the inaugural CONCACAF Nations League where not only is a championship on the line but we are able to play meaningful games in a competitive format," US coach Gregg Berhalter said.
"We've seen how valuable the Nations League has been for Europe and for this region it's another important opportunity to raise the level of competition.
"We aim to produce not only a good result but a good performance."
Berhalter took over the US team last December. He has gone 8-3 with one draw this year, losing to Mexico 1-0 in last month's Gold Cup final in the most recent match.
Before the Americans face Cuba, they will host Mexico on September 6 at East Rutherford, New Jersey, and entertain Uruguay on September 10 at St. Louis, Missouri. Both games are friendlies.