The bomb attack took place in the town of Manbij, controlled by the U.S.-backed Syrian Democratic Forces, while U.S. forces were conducting a routine patrol, officials said and Reuters reported.
This would be the deadliest attack on U.S. forces in Syria since they deployed on the ground there in 2015.
Photos and footage on social media show a large explosion on a busy street and wreckages that include human remains.
Three U.S. soldiers have died in Manbij alone, so far. A total of four lost their lives since 2015, when the U.S. sent troops on the ground in Syria.