Monitoring by U.S. military and intelligence assets has concluded that at least four missiles crashed as they flew over Iran.
The U.S. believes, based on intelligence reports of damage assessments, that some buildings were damaged and civilians may have been hurt.
It's unclear where in Iran the missiles landed. The Russian ships have been positioned in the south Caspian Sea, meaning the likely flight path for missiles into Syria would cross over both Iran and Iraq.
The Russians have been firing a relatively new cruise missile called "Kaliber," using it for the first time in combat.
The Russian Defense Ministry, however, took strong issue with the CNN report in a posting on Facebook Thursday.
"Unlike CNN, we don't report quoting anonymous sources, but we show launches of our missiles and the targets they hit in real-time mode," the statement reads, noting that Russian drones are operating in Syria around the clock, presumably monitoring operations.
It continues, "No matter how unpleasant and unexpected it is for our colleagues in the Pentagon and Langley, our strike yesterday with precision-guided weapons at ISIS infrastructure in Syria hit its targets."
In response, one U.S. official familiar with the intelligence reports told CNN, "These are the people who told us there were no little green men in Crimea."
The official was referring to Moscow's denials that men wearing green fatigues and using Russian weapons to fight the Ukraine government -- often dubbed "little green men" -- were in fact Russian soldiers. Moscow later annexed Crimea.
Iranian state TV, IRINN, reported later Thursday that an unnamed Iranian official also denied the CNN report.
Iran's semi-official FARS news additionally said that the Iranian Defense Ministry had rejected reports alleging that four of the 26 cruise missiles fired from Russia's Caspian fleet at ISIS targets in Syria have crashed in Iran. FARS added that the Iranian Defense Ministry said the reports are part of the West's "psychological warfare."
On Wednesday, Russian Defense Minister Sergey Shoigu told President Vladimir Putin on Russian television that all 26 missiles launched from four missile ships struck their targets, with no civilian facilities hit. Putin then congratulated him on the performance of the weapons.
It was not clear whether Shoigu was referring to the same missiles as the U.S. officials, as the latter may have been describing ones launched after the TV appearance.
The U.S. assessment of the off-target missiles came as Defense Secretary Ashton Carter warned Thursday at NATO headquarters in Brussels that Russia would likely suffer casualties "within the coming days" as it deepens its military involvement in Syria.
Carter also took rhetorical aim at Moscow Thursday, calling out Russia for "increasingly unprofessional behavior" after a Russian fighter jet violated Turkish airspace earlier this week and after Russia launched missiles into Syria from the Caspian Sea "without warning."
While Carter again pointed to the need for an agreement on "professional safety procedures" to avoid accidents in Syrian skies between Russian and U.S.-led sorties, which are taking aim at ISIS, he stressed that the U.S. would not cooperate militarily at a strategic level with Russia.
"We have not and will not agree to cooperate with Russia so long as they continue to pursue this misguided strategy," he said earlier in the week. "It remains our hope that Russia will see that tethering itself to a sinking ship is a losing strategy because Russia has the opportunity to change course and do the right thing. I don't know if they will."
In Rome earlier in his trip, Carter described to a "tragically flawed" Russian strategy in Syria, where Russian military actions appear increasingly aimed at bolstering the Syrian regime of President Bashar al-Assad in his struggle against rebel forces and less at fighting ISIS.
U.S. and Russian military officials have yet to establish a reliable communication channel to avoid potentially tragic accidents between Russian and U.S.-led forces operating in Syrian airspace.
State Department spokesman John Kirby declined to confirm that the Russian missiles had landed in Iran when asked about them at the daily press briefing Thursday, but he did say that such an incident would point to the need for better coordination.
"If something like that happened, again, I can't confirm it, but I think it points all the more towards the need to have proper de-confliction procedures in place," he said.
The U.S. and Russia did hold a high-level phone call Thursday. Secretary of State John Kerry and Russian Foreign Minister Sergey Lavrov spokes for about half an hour about Syria and Ukraine, according to Kirby.
Kerry reiterated U.S. concerns about the high number of non-ISIS targets that Russia has struck, he said. "They also talked about the importance of moving forward on tactical discussions and dialogue towards the goal of de-confliction, again to avoid mishaps and misunderstandings, particularly in the air."
Kerry also emphasized the need for a political solution to the civil war in Syria, which he said required a transitional government to move away from Assad.
Separately, a U.S. defense official told CNN that there have been at least two incidents in which Russian fighter jets flew in close proximity to U.S. drones. The first incident was not believed to be deliberate. However, the U.S. assessment is that the second encounter was a deliberate attempt to shadow the unmanned aircraft.
Unlike the recent encounters with manned U.S. fighter jets, the drones did not turn away, since no pilots were at risk.