The Syrian Observatory for Human Rights, a Britain-based war monitor, said regime forces had wrested back full control.
"Regime forces with Russian air cover were able to retake complete control of the town of Saraqeb on the Damascus-Aleppo highway," it said.
Syrian state news agency SANA said the army had re-entered the town after violent clashes against Turkey-backed opposition forces.
Opposition forces' spokesperson Naji Mustafa however said President Bashar al-Assad's forces had only taken part of the ghost town long emptied of its inhabitants.
"Assad's forces have launched an assault on Saraqeb and very violent clashes are ongoing inside," the spokesperson for the National Liberation Front said.
Pro-government forces for the first time in years wrested control of the town on February 8, but militants and allied forces then re-entered on Thursday.
Since December, Russia-backed regime forces have led a deadly military offensive against the last major opposition stronghold of Idlib, where Turkey supports some opposition groups.
The assault on the militant-dominated region has caused almost a million people to flee their homes and shelters in the middle of winter.
The Observatory said Damascus deployed regime troops and allied fighters from Lebanon's Hezbollah group as reinforcements to the Saraqeb area late on Sunday in preparation for an assault on the town.
Up to 23 militants were killed in Russian air strikes and clashes overnight, Observatory chief Rami Abdel Rahman said.
Violence has escalated between regime fighters and Turkish forces in the Idlib region in the past weeks, killing dozens of troops on each side.
On Sunday, Turkey confirmed a full military operation in northwest Syria after a Thursday air strike blamed on Damascus killed 34 Turkish soldiers.
The Observatory says more than 90 regime soldiers have been killed in Turkish bombardment since Friday, as have 10 allied Hezbollah fighters.
Saraqeb is a strategic prize for the Syrian government, as it seeks to revive a ravaged economy after nearly nine years of conflict.
The town lies at the intersection of the M5 and M4 highways, which connect the capital and regime coastal stronghold Latakia with second city Aleppo respectively.
On Sunday, SANA reported that the government shot down a Turkish drone near Saraqeb, publishing footage of an aircraft tumbling from the sky in flames.
The Syrian conflict has killed more than 380,000 people since it began in 2011.
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