Caleb Porter's side played on a cricket pitch in Guyana - and came away with a cricket score.
Despite issues with the field, playing on a cricket pitch at Guyana's national stadium, the Timbers had little trouble in the match. Steve Zakuani and Maximiliano Urruti scored in the first half, and although Barbosa Murillo pulled one back for the hosts in the 45th minute with an impressive free kick, Fenando Adi and Alvas Powell found the net after the break.
It was an impressive continental bow for the Oregon side, which took the longest flight in competition history and played its second game in four days after a clash with the New England Revolution in Massachusetts on Saturday.
The Timbers didn't have the biggest win of the night though, as Mexico powerhouse Club America put six past Puerto Rico's Bayamon FC with only one in reply.
The other MLS side in action on Tuesday, Sporting Kansas City, drew 1-1 with Real Esteli of Nicaragua.