Six Tupolev bombers flew out from a base in Russia on Tuesday morning and "made a concentrated strike with fragmentation bombs on (IS) facilities" east of Palmyra and the towns of Sukhna and Arak, it said on Facebook.
Russia gave advance warning to the US-led coalition, which is conducting a separate bombing campaign in the war-torn country, the ministry said.
The IS were forced out of Palmyra by Syrian regime forces in March, but Arak and Sukhna, both seized in the spring of 2015, remain in the rebels' hands.
Arak, located 35 kilometres (21 miles) east of Palmyra, is a small town that has strategic importance because of a nearby oil field, while Sukhna, 70 km northeast of Palmyra, is an IS bastion.
Russia said its strikes targeted sites that were "recently detected and confirmed through several intelligence channels."
The raids killed "a great number of personnel" and destroyed a field camp as well as three ammunition depots, three tanks and a dozen other vehicles, Moscow said.
All the aircraft returned to base successfully, the ministry said.
On Monday a group of IS fighters returned to Palmyra for the first time since March but were killed and their attack is now over, according to the Britain-based Syrian Observatory for Human Rights.
Two Russian pilots died on Saturday near Palmyra when their helicopter was shot down by IS fighters, bringing the total number of Russian troops killed in the Syrian conflict to 12.
A general view taken on March 27, 2016 shows part of the remains of Arch of Triumph, also called the Monumental Arch of Palmyra, that was destroyed by Islamic State (IS) group jihadists in October 2015 in the ancient Syrian city of Palmyra, after government troops recaptured the UNESCO world heritage site from the Islamic State (IS) group.
Russia on Tuesday bombed targets linked to the Islamic State (IS) group in Syria near the historic city of Palmyra, killing "a great number" of personnel, the defence ministry said.
