Shane Burger’s side had won their previous eight ODIs but never looked likely of chasing down a target of 311.
Sushant Modani top-scored with 77 and an unbeaten 60 from Gajanand Singh saw the USA post 310-5.
Scotland’s pursuit got off to a slow start, with just 27 scored in the first 10 overs as opener Matthew Cross fell for six.
Captain Kyle Coetzer made a resolute 28 and Calum MacLeod added 40, but the run-rate continued to creep up as Saurabh Netravalkar took four wickets.
George Munsey hit 54 off 53 balls, but it was not enough for Scotland as the USA – ranked 18th in the world, six places below Scotland – wrapped up a convincing victory.
The sides meet again at Moosa Stadium in Pearland, Texas, on Sunday and Scotland face the United Arab Emirates on Tuesday.
The Scots remain second in the table but with 16 games in hand on leaders Oman in the tournament that runs through to February 2023, with the top three progressing to the 2023 Cricket World Cup qualifier.
