Syrian government forces on Thursday raised the flag in the buffer zone separating Syrian-held territory from the Israeli Golan, the Syrian Observatory for Human Rights said.
But this month it became a new front for advancing Syrian forces after they re-established their authority over most of neighbouring Daraa province.
The wreckage and severe injuries made the full extent of the damage in Sweida hard to clarify, hours after the attacks.
The government controls nearly all of Sweida province but IS retains a presence in desert areas of its north and east.
Syrian state media aired graphic scenes of two blast sites within Sweida city, one showing the bodies of victims and another the aftermath of a motorcycle bombing that struck a busy vegetable market.
Government forces had driven the attackers away by late Wednesday night.
The onslaught began with a triple suicide bombing in the city of Sweida, which was followed by attacks with guns and explosives on villages to its north and east. At least 45 militants died carrying it out, the Observatory said.
The militants also swarmed several villages in the province's northeast, and in some cases, shot residents as they slept, according to activist-operated Facebook page Sweida News Network.
The attack by the IS came as Syrian government forces backed by Russian airpower continued their month-long military offensive to recover territory in southwest Syria bordering Jordan and the Israeli-occupied Golan Heights.
SNN said numerous dead were shot in the head as they slept.
Israel seized a large swathe of the Golan Heights from Syria in the 1967 Six-Day War and later annexed it.
Despite pro-government forces ousting ISIS from urban centers in eastern Syria a year ago, surprise raids in recent months have killed dozens of regime and allied fighters.
The extremist group boasted that its "soldiers" killed more than 100 people in Sweida.
The so-called Islamic State group has claimed responsibility for deadly raids and suicide blasts in Syria's southern Sweida province.