They were the group's deputy minister of war, who oversaw Mosul's capture in 2014, and a senior military commander, spokesman Peter Cook said.
US-led air strikes have helped Iraqi forces and its allies to push IS back.
An offensive to retake Mosul is seen as the next battle for Iraqi forces.
Basim Muhammad Ahmad Sultan al-Bajari was a former al-Qaeda member who also led an IS battalion known for using homemade explosives, suicide bombers and mustard gas in its attacks, Mr Cook said in a statement.
Hatim Talib al-Hamduni was a military commander in Mosul and the head of military police in the region, he added.
"Their deaths, along with strikes against other ISIL leaders in the past month, have critically degraded ISIL's leadership experience in Mosul and removed two of their most senior military members in northern Iraq," Mr Cook said, using another acronym for IS.
They were both killed as a result of a "precision strike" on 25 June, he said.
IS launched a sweeping offensive in June 2014, overrunning large areas in northern and western Iraq and eastern Syria, establishing a self-declared "Islamic Caliphate" in the land it captured.
But the Sunni jihadist group has recently lost large parts of the territory it once controlled, including the Iraqi cities of Falluja and Ramadi.
Mosul, Iraq's second largest city, has been under IS control since 2014 and the Iraqi army launched an operation in March aiming to retake it.
Two million people lived there before the group took it over.
Two senior military leaders of so-called Islamic State (IS) were killed by a US-led coalition air strike near the northern Iraqi city of Mosul, the Pentagon says.