Pochettino said some players were tired after their 1-1 draw with Ecuador in Austin, Texas, on Friday and should not be risked for the high-altitude match at Denver.
"We need to pay attention that we change from Austin to Denver. The conditions are completely different," the Argentine told reporters after training on Monday.
"You saw, we suffered.
"It’s a good opportunity also to keep improving and showing, maybe, different approaches to the game ... For sure, there are going to be changes, and maybe change the shape."
Key attacker Christian Pulisic was brought on late against Ecuador after suffering some ankle swelling in the lead up to the match, but trained on Monday and is available for selection.
However, left back Antonee Robinson will miss out again for the World Cup co-hosts. The Fulham defender is still sore from a knee problem despite his call-up for the October international window.
"Hope that it’s not an important thing but (that) he’ll go back to his club in a normal way there training and competing," said Pochettino.
The USA face an Australia side who beat World Cup co-hosts Canada 1-0 in Montreal at the weekend and have not lost a game under Popovic since he took over from Graham Arnold a year ago.
Australia qualified mid-year for the 2026 showpiece in North America and have enjoyed the freedom to build depth and bed down combinations.
While Pochettino has repeatedly played down the importance of results until the World Cup, Popovic said the Socceroos were taking every friendly seriously.
"We want to win every game. It's always easy to say, when you don't get a result, that the result doesn't matter because it's a friendly," he told reporters.
"We want to keep our run going. We know it will be difficult and that's why we've taken on this game."
With Dick's Sporting Goods Park sitting more than 5,200 feet (1,584m) above sea level, the highest elevation among Major League Soccer stadiums in the U.S., Popovic said he would also make changes given the tight turnaround since Canada.
"We welcome that (physical) test and we'll learn a bit about the players," he added.
"We learned a lot the other night where we know that they were struggling, a lot of them, physically to get through at the level we wanted.
"But they showed another side of their personality and character that helped them get through.
"So if we can match those two (aspects) together come June next year, we'll be in a good position."