Those analysts believe al-Qaduli would have been expected to take control of the day-to-day running of ISIS, also called ISIL, if its leader, Abu Bakr al-Baghdadi, was killed or incapacitated.
The U.S. operation was intended to capture him alive, a U.S. official told CNN. Helicopters loaded with special operations forces swooped in on a vehicle carrying al-Qaduli, but at the last moment something happened that caused them to decide to fire on the vehicle instead. The official would not say what it was that caused them to modify the plan.
Defense Secretary Ash Carter announced the death at a news conference Friday morning.
"We are systematically eliminating ISIL's cabinet," Carter said, adding it was "the second senior ISIL leader we've successfully targeted this month."
Explaining the significance of this particular figure, Carter noted, "We've taken out the leader who oversees the funding for ISIL's operations, hurting their ability to pay fighters and hire recruits."
Asked whether the U.S. was turning the corner on the fight against ISIS, Carter responded, "We're certainly gathering momentum and we're seeing that that momentum is having an effect."
Chairman of the Joint Chiefs Gen. Joseph Dunford, appearing alongside Carter, agreed that the U.S.-led coalition was gaining momentum, but he cautioned: "By no means would I say that we're about to break the back of ISIL or that the fight is over."
Carter also connected Friday's announcement to the terror attacks in Europe that ISIS has undertaken, including a mass killing in Brussels on Tuesday.
"Like Paris, Brussels is a strong reminder of why we need to hasten the defeat of ISIL wherever it exists in the world," Carter said, stressing the United States' commitment to Europe.
"Our enemies are one and the same," he declared."And together we continue to do more and more to bring the full weight of our vast military capabilities to bear in accelerating the defeat of ISIL."
This is not the first time al-Qaduli has been reported killed. In July, the Iraqi Defense Ministry claimed a coalition air strike had killed him in Tal Afar in northern Iraq.
At the time U.S. Central Command, which oversees military operations in the region, debunked the claim, saying it had "no information to corroborate" that ISIS' second-in-command had been killed.
The U.S. Treasury labeled al-Qaduli "a specially designated global terrorist" in 2014. According to the Treasury, he also goes by 12 aliases, including Hajji Iman, a name Carter used when speaking to reporters Friday.
The U.S. State Department had offered a $7 million reward for information on al-Qaduli -- the highest for any ISIS leader apart from al-Baghdadi, who is valued at $10 million.
That sizable bounty makes al-Qaduli the sixth-most-wanted terrorist in the world, ranking only behind the likes of the heads of al Qaeda, ISIS and the Taliban's Haqqani network.
Al-Qaduli was born in Mosul, Iraq's second-largest city, in either 1957 or 1959.
He initially joined Al-Qaeda in Iraq -- the group that would evolve into ISIS -- in 2004, serving as a top deputy to then-leader Abu Musab al-Zarqawi and emir of the group's Mosul branch.
He was captured and jailed by Iraqi authorities but was released in 2012, at which point he rejoined the terror group in Syria, according to the U.S. State Department.
Al-Qaduli is also believed to go by the name Abu Alaa al-Afri, but CNN cannot independently confirm that that is the same person.
Al-Afri is reputed to have been a physics teacher and a favorite of al-Qaeda leader Osama bin Laden.
He is an ethnic Turkmen, which analysts say was a barrier that could have prevented him from succeeding ISIS leader Abu Bakr al-Baghdadi.