Defender Cristian Romero opened the scoring in the 16th minute with Enzo Fernández in the 42nd and Giovani Lo Celso in the 52nd completing the victory at Lincoln Financial Field, home of the NFL's Philadelphia Eagles.
Messi, the eight-time Ballon d'Or winner now starring for Major League Soccer's Inter Miami, was ruled out of Friday's match and Argentina's friendly against Costa Rica in Los Angeles next week after tweaking a hamstring in Miami's 3-1 victory over Nashville in the CONCACAF Champions Cup this month.
On a chilly night in Philadelphia, Argentina didn't need him to comfortably win their first friendly of the year against a team that has now gone 21 matches without a win.
Romero was the first to break through against the team coached by Spain's David Doniga, rising to head home a corner kick taken by Angel Di Maria.
Minutes before half-time, Di Maria received the ball on the right flank and set up Rodrigo de Paul, whose back pass was headed by Lo Celso to Fernandez who slotted home from in front of the goal.
After the break. it was Lo Celso's turn as he finished off another brilliant connection between Di Maria and Lautaro Martinez with a left-footed shot.
The match saw Argentina manager Lionel Scaloni take the opportunity to give minutes to youngsters Alejandro Garnacho and Valentin Barco - the 19-year-old left-back signed by Brighton in January who stood out for the U-23 team in qualifying for the Paris Olympics.
