In the worst violence to hit the area since the country's conflict began, the militants also reportedly abducted at least 18 people, activists said.
The high death toll includes victims killed by three suicide bombings in Sweida, and those who held arms to face the IS attacks on towns in the northeastern countryside of Sweida.
Hassan Omar, a local health official in Sweida province, said on Thursday that at least 150 people were wounded in the attacks; some of them were in critical condition. Until these attacks, Sweida has been one of the few areas of relative peace during the civil war.
The attacks are the worst in months
Pro-government forces ousted IS from urban centres in eastern Syria previous year, but IS raids in recent months have killed dozens of regime and allied fighters.
After air raid sirens sounded in the south of the Israeli-occupied Golan Heights, the army said rockets had been fired from Syria towards Israel.
Israel took control of 1,200 square kilometers (460 square miles) of the Golan from Syria during the 1967 Six Day War and later annexed it in a move never recognized internationally.
The announcement came following reports of Russian resentment after Israel shot down a Syrian Sukhoi fighter jet, which Damascus had said was conducting military operations against ISIS positions in the province of Quneitra.
Islamic State lost almost all the territory it once held in Syria past year in separate offensives by the Russian-backed army and a USA -backed militia alliance.
Under the terms of a 1974 United Nations armistice that demilitarised much of the Golan, Israel withdrew from the abandoned capital of Quneitra province which it had razed to the ground after capturing it in the 1967 Arab-Israeli war.
Also on Friday, Syrian army troops scored progress in the fight against Daesh Takfiri terrorists at Yarmouk basin in the southern countryside of Dara'a province.
IS later claimed responsibility for the attacks via the group's outlet on the messaging app Telegram.
The wreckage and severe injuries made the full extent of the damage in Sweida hard to clarify, hours after the attacks.
In the city itself, at least two attackers blew themselves up, one near a marketplace and the second in another district, state television said.
The army and villagers regained control of a hill and broke a brief siege of another nearby village after clashes, Ikhbariyah said.
ISIS killed dozens of people in a string of attacks on government-held parts of the southwest.