A total of 10 Kalibr missiles were fired at ISIS command centres, ammunition dumps and hangars being used to store armoured vehicles, Russian defence officials said.
Footage of the launch shows the weapons suddenly blasting through the sea while the submarines remain hidden.
Russian news agencies cited General Igor Konashenkov as saying the two subs, ‘Velikiy Novgorod’ and ‘Kolpino’, were targeting militant positions outside the town of Meyadin, in eastern Syria.
Today’s launch was the latest in a series of Russian strikes in support of Syrian Army forces, which are fighting a major offensive against ISIS.
Russian defence officials said airstrikes around the city of Deir ez-Zor – about 25km from Meyadin – had this week destroyed a major militant command centre as well as the terrorist group’s “largest underground ammunition depot”.
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However, Al Jazeera reported the Syrian opposition as saying the bombings were a “horrific massacre against those fleeing in the suburbs of Deir ez-Zor”.
A statement from the opposition, said: ”The warplanes of the Russian occupation committed a monstrous massacre near al-Ashira city south of Deir ez-Zor, which led to the killing of no less than 50 civilians, mostly women and children.”
Last month, former Russian minister of defence, Sergey Shoygu, said the fall of ISIS in Deir ez-Zor could be the end of the self-proclaimed caliphate.
He added: “There have been military actions for more than one year. People bravely fight there.
“Regularly, two or three, or it happens, four times a week, food, medicine, ammunition are being delivered there.
“This is perhaps the main point at the Euphrates, which will in many ways indicate the end of the fight against ISIS.”
The Russian-made Kalibr cruise missile has a range of up to 660km and can be tipped with conventional explosives or nuclear weapons.
In April, the United States unleashed a barrage of 59 Tomahawk cruise missiles against a Syrian Government airfield.
The attack was in response to a chemical weapons attack by Syrian leader Bashar al-Assad which killed more than 70 people.