A first-half goal blitz from Pochettino's side laid the foundations for an emphatic victory in Tampa against Marcelo Bielsa's overwhelmed Uruguay line-up.
World Cup co-hosts the United States raced into a 4-0 lead just before half-time thanks to a goal from Sebastian Berhalter, two goals from Alex Freeman and a 42nd-minute strike from Diego Luna.
Although Giorgian de Arrascaeta pulled a goal back in first-half stoppage time for Uruguay, Pochettino's team completed the rout with a 68th-minute Tanner Tessmann goal.
It was the first time the United States has ever scored five goals against a World Cup-winning nation and was further evidence that Pochettino's squad is on an upward curve after a bumpy start to the Argentine coach's reign.
US goalscorer Berhalter, the son of former US coach Gregg Berhalter, had set the ball rolling with a sensational strike in the 17th minute, curling a sweetly struck shot into the far corner after a cleverly worked free kick routine.
"We wanted to make a statement," Sebastian Berhalter said afterwards.
"We wanted to show what US soccer is about. We had a chance to go out here and give everything we had and we were ready against a good Uruguay team," the Vancouver Whitecaps midfielder added.
"We just wanted to make the fans happy - to give them something to believe in and hopefully tonight we went out there and did that."