Khamenei, speaking to a group from Iran's religious capital of Qom, made the remark while recounting a story about a U.S. official once predicting he'd celebrate Christmas in Iran.
"Some U.S. officials pretend that they are mad," Khamenei said. "Of course I don't agree with that, but they are first-class idiots."
Iran's supreme leader, viewed by Shiite hard-liners as second only to God, typically doesn't make such forceful remarks. However, Trump's decision last year to withdraw from the nuclear deal has seen the 79-year-old cleric grow increasingly critical.
In 2017, Khamenei dismissed remarks by Trump calling Iran a "terrorist" nation as "idiotic." Last May, after Trump withdrew from the nuclear deal which saw Iran limit its uranium enrichment in exchange for the lifting of economic sanctions, Khamenei told Trump in a speech: "You cannot do a damn thing!"
"The body of this man, Trump, will turn to ashes and become the food of the worms and ants, while the Islamic Republic continues to stand," Khamenei said at the time.
Khamenei's comments Wednesday came as Pompeo visited Iraq. On Tuesday, the U.S. top diplomat threatened that America would double down on commercial and diplomatic efforts in the coming weeks to "put real pressure on Iran."
Khamenei's remarks to Qom residents were meant to mark the anniversary of religious riots in 1978 that challenged Shah Mohammad Reza Pahlavi. They would spiral into the nationwide demonstration that saw the shah leave Iran and give rise to the 1979 Islamic Revolution. Iranians will commemorate the revolution's 40th anniversary in February.