The comments by Russian Foreign Minister Sergei Lavrov came days ahead of scheduled Moscow talks between Russian President Vladimir Putin and a Syrian delegation.
"Possibly... this is not so much an operation against Islamic State as the preparation for an operation to change the regime surreptitiously under the cover of this anti-terrorist operation," Lavrov told a forum of politics experts in Moscow, quoted by TASS news agency.
He accused the US of having "perverted logic" over Assad, saying Washington blamed the Syrian leader's regime for the flood of militants arriving in the region.
"The Americans say that Assad's regime is a very important factor that brings terrorists to the region to try to topple him. I think this is absolutely perverted logic," Lavrov said.
Moscow has been a staunch ally of Assad's regime throughout Syria's civil war and has repeatedly thwarted UN action against him.
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Lavrov claimed that his US counterpart John Kerry told him that Washington did not get a mandate for the anti-IS operation from the US Security Council because this would require "defining the status of Assad's regime somehow."
"Syria is a sovereign country, a member of the UN. This is not right," Lavrov said.
"The Americans have talked and are talking even with the Taliban. When it needs to be, the United States is very pragmatic. So why is the approach to Syria still ideologised to the hilt?"
The Russian foreign ministry said that Lavrov and Kerry held telephone talks on Friday in which they discussed the need for "renewing as soon as possible... the search for political and diplomatic ways to overcome the Syrian crisis and unite the efforts of the global community to fight terrorism on a stable basis of international law."
A Syrian delegation headed by Foreign Minister Walid Muallem is to meet Putin in Moscow on Wednesday to discuss a possible relaunch of peace talks with the opposition.
Russia and Saudi Arabia said Friday that they backed a revival of the so-called "Geneva 1" peace plan calling for a transitional government which was the result of talks held in summer 2012 in the Swiss city.