For their efforts, Uruguay, who have played in four World Cups, have qualified for the first time in the Americas 1 position and find themselves in the same group as New Zealand, host nation France and Italy, with one other qualifier from Africa One.
Chile kept their hopes of a first appearance at a World Cup alive when twice beating Canada, 22-21 and 33-24, to deny Canada a World Cup place for the first time.
USA Eagles head coach Gary Gold, the former Springboks assistant coach, said: "Obviously an incredibly disappointing day and very disappointing result.
"Most certainly not what we planned for as I thought the week's preparation went well, under the circumstances of us having to travel late.
"Yet again, we seem to be the masters of our own destiny by making errors at critical times. We knew that Uruguay were always going to be a commanding force at home, with a very passionate crowd, and that was a really good challenge for us to have to endure," he said.
"I think we made life particularly difficult for ourselves by not converting a really good lead last week at Glendale, and that's how these aggregate games work. You need to take your opportunities when you have them. We didn't do that last week and we paid the price this week."
The Eagles had shown their character by not giving up, he said.
"These are very tough lessons for us to be learning, but I know this young team is going to be very good one day because of the lessons that we are learning. Unfortunately, that's how sport works. We need to learn these tough lessons in order for us to grow as an organisation, and that will come," he said.