Syrian rebel forces advanced on the central city of Homs and Kurdish fighters seized effective control of the eastern desert, jolting President Bashar al-Assad's grip on power and triggering local revolts against his rule in the south.
If Islamist insurgents captured Homs in their lightning new offensive, it would cut off the capital Damascus from the coast where his Russian allies have a naval base and air base.
In a parallel setback for Mr Assad, a US-backed alliance led by Syrian Kurdish fighters took Deir el-Zor, the government's main foothold in the vast desert in the east of the country, three Syrian sources told journalists on the ground.
It was the third major city, after Aleppo and Hama in the northwest and centre, to fall out of Mr Assad's control in a week.
Piling on the pressure, two Syrian army sources said the alliance known as the Syrian Democratic Forces (SDF) had swept through the nearby Albu Kamal border crossing with Iraq.
After years locked behind frozen front lines, rebel forces have burst out of their northwestern Idlib bastion to achieve the swiftest battlefield advance by either side since a street uprising against Mr Assad mushroomed into civil war 13 years ago.
The Syrian leader regained control of most of the country after key allies - Russia, Iran and Lebanon's Hezbollah group - came to his rescue.
However, all have recently been weakened and diverted by other crises, giving sunni muslim militants a window to fight back.
A senior Iranian official meanwhile said Iran, which has been focused on tensions with arch-foe Israel since the Gaza war began, would send missiles, drones and more advisers to Syria.
The head of the Syrian faction leading the sweeping assault told CNN that his group - a former Al-Qaeda affiliate now known as Hayat Tahrir al-Sham (HTS) - aimed to "build Syria" and bring Syrian refugees back home from Lebanon and Europe.
It was Abu Mohammed Al-Golani's first interview since his group began seizing territory from Mr Assad's forces on 27 November.
Rebels have captured two major cities so far and are now thrusting toward the key crossroads city of Homs.
HTS, which broke from Al-Qaeda in 2016, says it poses no threat to the West and has spent years trying to moderate its image, presenting itself as a viable alternative to the Assad family's 54-year authoritarian rule.
Surprise offensive
The rebels' sweep has taken the region by surprise and emboldened other opponents of Assad. Syrian rebel commander Hassan Abdul Ghany urged top military officers to defect, in a video statement.
At least three people were killed in clashes between Druze militias and security forces in the southern Syrian city of Sweida, two witnesses and a local activist said.
The Israeli military said it was reinforcing aerial and ground forces in the Israeli-occupied Golan Heights in southwest Syria and was prepared for all scenarios.
Iran-backed Hezbollah, meanwhile, sent a small number of"supervising forces" from Lebanon to Syria overnight to help prevent anti-government fighters from seizing Homs, two senior Lebanese security sources told Reuters.
However Israel has seriously weakened Hezbollah in fighting inLebanon this year, assassinating its top officials and devastating its military infrastructure.
HTS rebels said they had also taken over the towns of Tabisa and Rastan, bringing them within kilometres of Homs.
The Syrian military said there was no truth to reports it had withdrawn from Homs, saying in a statement it was deployed along "steady and solid defence lines" there.
The Syrian Observatory for Human Rights, a UK-based monitoring group, said thousands of people had begun fleeing from Homs last night towards the Mediterranean coastal regions of Latakia and Tartus, strongholds of the government.
Islamic state
In another alarming development for Mr Assad, the head of the US-backed Syrian Kurdish force said the Islamic State group, which imposed a reign of terror over swathes of Iraq and Syria before its defeat by a US-led coalition in 2017, had now taken control of some areas in eastern Syria.
"Due to the recent developments, there is increased movement by Islamic State mercenaries in the Syrian desert, in the south and west of Deir Al-Zor and the countryside of al-Raqqa," Mazloum Abdi told reporters, referring to areas in Syria's east.
Rebels led by HTS have sought to capitalise on their swift takeover of Aleppo in the north and Hama in west-central Syria by pressing onwards to Homs, another 40km south.
A rebel operations room urged Homs residents in an online post to rise up, saying: "Your time has come".
