The shock attack comes despite a Russian air campaign targeting the group that began in September, and more than a year of strikes by a US-led coalition against the jihadists in Syria.
The Britain-based Syrian Observatory for Human Rights said IS had killed at least 135 people in the multi-front attack that began on Saturday.
The dead included 85 civilians and 50 regime fighters, according to the monitor, which said Sunday that IS had also kidnapped more than 400 civilians from captured territory.
"Those abducted, all of whom are Sunnis, include women, children and family members of pro-regime fighters," Observatory chief Rami Abdel Rahman said.
He said they had been taken to areas under IS control in the west of Deir Ezzor province and to the border with Raqa province -- the main IS stronghold in Syria -- to the northwest.
The monitor said at least 42 IS fighters had been killed in the attack, adding that fighting was ongoing on Sunday, with regime forces backed by Russian air strikes trying to recapture lost ground.
Syria's state news agency SANA said at least 300 civilians, "most of them women, children and elderly people," had been killed in the assault.
It denounced the deaths as a "massacre".
- History of mass murders -
The IS assault puts the group in control of around 60 percent of Deir Ezzor city, which is capital of the surrounding province of the same name, an oil-rich region that borders Iraq.
The jihadist group already controls most of the province, but regime forces have clung onto part of the city and a neighbouring air base despite repeated IS attacks.
If confirmed, the death toll in the assault would be one of the highest in a single attack by IS, though the jihadists have carried out mass murders before.
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In 2014, its fighters killed hundreds of members of the Sunni Shaitat tribe in Deir Ezzor province after they opposed the jihadists.
And in August 2014, the group massacred some 200 Syrian soldiers when it overran the Tabqa military base in Raqa province.
The jihadists have also carried out mass abductions before, seizing more than 200 civilians from central Homs province in August 2014, and at least 220 Assyrian Christians from villages in the northeast of the country months earlier.
Some of those abducted in those incidents have been freed in small batches, in some cases reportedly in exchange for ransoms.
The assault came despite a Russian air campaign that began in September in support of the government, which Moscow says targets IS and other "terrorist" groups.
- IS under pressure -
The Russian strikes have so far killed at least 808 IS fighters, according to the Observatory, though they have also killed moderate and Islamist fighters and civilians, it says.
More than 3,700 IS jihadists have also been killed in US-led coalition strikes that began in Syria in September 2014.
On Sunday, the Observatory said 40 civilians including eight children had been killed in strikes on the IS bastion of Raqa city.
The monitor said it was unclear if the strikes were carried out by regime or Russian planes.
In recent months, IS has come under pressure particularly from Kurdish fighters backed by US strikes, and more recently regime forces supported by Russian air raids.
On Saturday, at least 16 IS fighters were killed in a failed attack on a government position in Aleppo province, where loyalist troops and pro-regime fighters have been advancing towards the group's stronghold of Al-Bab.
Regime forces are now within 10 kilometres (six miles) of Al-Bab, and are seeking to sever IS-held territory in Aleppo province from that held by the group in neighbouring Raqa.
More than 260,000 people have been killed in Syria since the conflict began in March 2011 with anti-government protests.