The US time of three minutes 40.28 seconds broke the previous record of three minutes 41.71 seconds set by Great Britain at the 2015 world championships.
USA set new world record in 4x100m Mixed Medley
Ryan Murphy, Kevin Cordes, Kelsi Worrell and Mallory Comerford were in stunning form with Australia the only country within four seconds of the American team.
US Kevin Cordes competes in the men's 50m breaststroke semi-final during the swimming competition at the 2017 FINA World Championships in Budapest.
Image credit: Eurosport
The final is due to be staged in the evening session at the Duna Arena.
The mixed medley relay was added to the World Championships two years ago, and is set to become part of the 2020 Tokyo Olympics for the first time.