A spokesperson for US Central Command said: "A US service member died from wounds sustained in an explosive device blast outside of Mosul, Iraq, on Saturday."
No further information was immediately released, but the blast came after a number of deaths and injuries caused by mines and improvised explosive devices littering Isis' former territories.
The terrorist group is known to rig buildings, cars and even toys and items of food and drink with explosives as it retreats.
The tactic has slowed the advance on Mosul, which started on the city's outskirts in October 2016, and prevented civilians from immediately returning to their homes.
Military commanders were forced to temporarily pause the offensive last month amid "catastrophic" civilian casualties caused mainly by artillery and air strikes.
Isis has also murdered countless civilians found attempting to flee, as well as posing as Iraqi soldiers to dupe civilians who were then massacred.
Members of international organisations and militaries have been bolstering the de-mining effort surrounding the city as fierce fighting continues in Isis' remaining western districts.
Another American soldier was killed by an improvised device near Mosul in October, while helping government guide US air strikes embedded with Iraqi and Kurdish Peshmerga forces.
Two members of US special forces were also killed in Afghanistan on Wednesday, during a possible "friendly fire" incident during a night raid on an Isis compound.
The latest casualty came a day after Isis killed at least four people and wounded several more at a police station in central Baghdad.
A suicide car bomb was detonated outside the building in Karrada district, officials said.
Iraqi and coalition officials have warned that as Isis loses ground in Iraq and Syria, the group will increasingly return to its insurgent roots.
Analysts say terrorists are attempting to inspire attacks on civilians around the world in a bid to retain legitimacy and support.