Three air strikes were conducted in the country, including one on an oil collection point, another on an IS tactical unit and a third on an IS armoured personnel carrier, according a statement issued by the US military's Central Command.
Australian defence Minister Kevin Andrews confirmed an Australian F/A-18 Super Hornet fired a missile during the operation.
"Two days ago, the Air Task Group completed its first strike against a Daesh (IS) strike in eastern Syria, destroying an armoured personnel carrier," he said.
"Two of our Hornets identified the personnel carrier, which was hidden in a Daesh compound.
"That information was reported back to the combined operations centre by our Wedgetail command and control aircraft, and upon receiving authorisation to proceed, one of the Hornets employed a precision guided weapon to destroy the target."
Mr Andrews said Australian fighter jets were never in any risk of enemy fire during the operation, and that strict controls were in place to limit civilian casualties.
"This was done from a distance or height that preserved the safety of the Australian aircraft," he said.
"We work within very strict rules of engagement, and those rules of engagement are to ensure as far as possible that we don't have unwanted civilian casualties.
"Sorties are being flown over Syria and Iraq, the majority of our missions are still over Iraq and we're doing them on a very regular basis."
US Central Command released information on the air strike overnight, and the Minister was asked why the Australian government delayed releasing details of the operation.
"We don't normally announce the missions that occur almost on a daily basis," Mr Andrews said.
"On this occasion, I was planning to make a ministerial statement, which is a six-monthly update of our operations in the Middle East and that's due today."
The US statement, issued by the Combined Joint Task Force in charge of Operation Inherent Resolve, confirmed Australia was among the nations whose warplanes had carried out the air strikes inside Syria.
The other countries listed as having taken part to date were Bahrain, Canada, Jordan, Saudi Arabia, Turkey, the UAE and the US.
The statement also listed 15 air strikes which had been carried out against IS in Iraq.
Last week the Federal Government announced that Australia's air campaign against IS would be expanded beyond Iraq to include parts of Syria, where Islamic State militants have seized large areas of territory amid a raging civil war.
Russian president Vladimir Putin has promised to continue offering military support to Bashar al-Assad's government and has urged other countries to follow suit, after the US and Europe voiced concern over Russia's escalating military support for the Assad regime.