Brett Morris and Jarryd Hayne scored four tries each, matching the record for an Australian in a Test match, as the Tomahawks' World Cup fairytale came to a brutal end in front of 5762 fans in Wrexham, Wales.
The win set up a semi-final showdown with either Samoa or Fiji at Wembley next week but the tournament favourites' title hopes may have suffered a significant blow with Slater's injury.
The Melbourne Storm star's week from hell continued as he was carried off the field just after halftime with a knee injury.
Slater hurt his left knee after fielding a bomb and copping a heavy shot from US forward Roman Hifo and it is the same knee he injured in last year's State of Origin series.
Kangaroos coach Tim Sheens was upbeat Slater could be back for the final.
"It's an injury to his old injury," Sheens said. "He's got no PCL (posterior cruciate ligament) so he can't hurt it, it's just a matter of if there's any other damage.
"We're just hoping it's a bad knock but he's going for an MRI, we'll know tonight. We've got our hopes up ... we hope he might still be available. I'm not going to panic just yet."
"The issue is the knock and how much damage it's done, if it's cartilage damage or if it's just bruising on the bone - which we're hoping it is."
The injury came on the back of a dramatic week for Slater, who was arrested but released without charge after being involved in a nightclub fight in Manchester early on Monday morning.
Australia at least have no shortage of fullbacks if Slater is ruled out with Greg Inglis and Hayne at their devastating best playing in the centres on Saturday.
Along with his four tries, Hayne set up several others to justify his surprise selection ahead of specialist centres Brent Tate, Josh Morris and Michael Jennings while Inglis had a double.
Hayne played a crucial role as Morris bagged four tries in the space of 18 minutes to help Australia to a 38-0 lead at the break.
The St George Illawarra winger became the seventh Australian to score four tries in a Test match before Hayne became the eighth.
Cameron Smith and Cooper Cronk also scored tries for Australia.
The Tomahawks, who defied their 500-1 tournament odds to reach the last eight, tried hard but the Kangaroos did not concede a try for the third straight match.
"I'm no less proud of what these guys have done, we won't draw too much on what happened today," USA coach Terry Matterson said.
"What we've done over the last four weeks is very special and I'll always hold it very close to my heart."
The USA were on the back foot right from the opening whistle as Smith's kick-off bounced off the crossbar and into Australia's possession.
Johnathan Thurston had an off first half with the boot but recovered to convert seven of Australia's 12 tries.
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