At least 215 people were killed and 180 wounded, the head of the local health authority told pro-government media.
The wreckage and severe injuries made the full extent of the damage in Sweida hard to clarify, hours after the attacks.
The southern province of Sweida is largely held by the government, but IS retains a presence in a northeastern desert region.
Al-Ikhbariya said one of the suicide bombers hit a vegetable market in the city of Sweida just after 5 a.m., a busy time for the merchants at the start of their day.
After Wednesday attack, some tribal leaders in Sweida said hundreds of young men are ready to take part in defeating IS in the areas they stormed in the countryside of Sweida.
A number of civilians were killed and others were injured on Wednesday morning in terrorist attacks on the city of Sweida synchronizing with terrorist attacks on a number of villages in eastern and northern rural areas. At least 45 militants died carrying it out, the Observatory said.
An activist-operated Facebook page called Sweida News Network said numerous killed were shot in the head.
"They kidnapped more than 40 people, all of them women or children", said Bou Ammar. It said the dead included at least 35 civilians.
Government troops and allied forces hold all of Sweida province except for that enclave.
The air force struck militant hideouts there after soldiers thwarted an attempt by fighters to infiltrate the three village, state media said.
Syrian forces have retaken territory from the militants in recent weeks, particularly west of Sweida near the Israeli-occupied Golan Heights. The SNN said the militants sneaked into the villages under the cover of darkness, shooting residents as they slept.
ISIS was driven from almost all the territory it once held in Syria past year in separate offensives by the Russian-backed army and a US -backed militia alliance.
Despite pro-government forces ousting the group from urban centres in eastern Syria previous year, surprise IS raids in recent months have killed dozens of regime and allied fighters.
More than 350,000 people have been killed and millions displaced since Syria's war started in 2011.
Hizbullah issued a statement on Thursday condemning the suicide bombings that killed around 250 individuals overnight in Syria's Sweida province.