The KC-135 aircraft was part of the operation against Iran, but the crash was not due to hostile fire or friendly fire, it said in a statement.
US Central Command, which oversees the Middle East, said two aircraft were involved and one landed safely while the other went down in western Iraq. It described the latter as "a loss".
A US official, who spoke on condition of anonymity, said the other plane involved also was a KC-135 tanker.
"More information will be made available as the situation develops," Central Command said in a statement. "We ask for continued patience to gather additional details and provide clarity for the families of service members."
It wasn't immediately clear if there were any casualties. Both US President Donald Trump and Defence Secretary Pete Hegseth have warned the Iran war would likely claim more American lives before it ends.
The tanker is the fourth publicly acknowledged aircraft to crash as part of the US military's operations against Iran. Last week, the military confirmed three American fighter jets were mistakenly downed by friendly Kuwaiti fire.
All six crew members safely ejected from the F-15E Strike Eagles and were in stable condition after being recovered, the US said.
Seven American troops have been killed in combat during the Iran war so far. Six of the service members were killed when an Iranian drone struck an operations centre at a civilian port in Kuwait.
The seventh died after being wounded during an attack on the Prince Sultan Air Base in Saudi Arabia.
About 140 US service members have been wounded, including eight severely, the Pentagon said earlier this week.
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