A Pentagon spokesperson said the trucks were hit in a single air strike near the IS-held town of Albu Kamal, according to AFP news agency.
The coalition has targeted fuel trucks before, but a coalition official said this was the most they had hit at once.
Black market trade in oil is one of IS' most important sources of funding.
It is believed to make about $500m (Â£329m) a year from the oil industry in territory under its control.
The trucks were parked in a loading area, being filled or about to depart, when they were hit, the coalition spokesman told AFP.
The coalition began air strikes on IS-held oil infrastructure last year, and last month the US vowed to be "more aggressive" in targeting IS oil.
The Pentagon spokesperson said Sunday's attack "was part of that strategy to start degrading their financial ability".
The US-led coalition destroyed 116 fuel trucks operated by so-called Islamic State (IS) in eastern Syria in one day, US defence officials say.