At least 33 Turkish soldiers were killed in an air strike by Syrian government forces in northwestern Idlib province as Turkey vowed "to respond in kind" with attacks on "all" their positions.
The rapid escalation of the conflict on Friday also threatened another refugee crisis as media reports cited Turkish officials as saying they "opened the gates" for Syrian refugees to transit unimpeded to Europe.
"Despite warnings after the first strike, the Syrian regime unfortunately continued its attacks, even targeting ambulances," Defence Minister Hulusi Akar said on Friday, adding retaliatory attacks killed "309 regime troops".
Al Jazeera could not immediately confirm the reported deaths.
"Turkish forces destroyed five Syrian regime choppers, 23 tanks, 10 armored vehicles, 23 howitzers, five ammunition trucks, a SA-17, a SA-22 air defense system as well as three ammunition depots," Akar added.
Russia said Ankara failed to inform it that Turkish troops were fighting alongside rebels in Idlib - comments denied by Turkey.
"Turkish soldiers who were in the battle formations of terrorist groups came under the fire of Syrian troops," Russia's defence ministry said in a statement.
Russian state television reported Turkish military specialists were using shoulder-fired missiles to try to shoot down Russian and Syrian military aircraft over Idlib.
The deaths were the largest number of fatalities suffered by Turkey in a single day since it first intervened in Syria in 2016. In response, Turkey warned it will attack "all known targets of the Syrian regime".
"The Assad regime represents a threat to our national security, the region and Europe since it began acting like a criminal network terrorising its own citizens," Fahrettin Altun, the head of Turkey's presidential communications department, told Al Jazeera.
"The regime has taken advantage of the international silence in the face of its crimes for years."
Retaliatory drone and artillery strikes hit Syria army positions in southern and eastern parts of the province, the Syrian Observatory for Human Rights war monitor said.
Fighting took place during a Russia-backed Syrian government offensive to seize the war-torn country's last opposition-held stronghold, which is home to more than three million people.
The ferocious bombing campaign and ground assault have displaced nearly one million people since December, more than half of whom are children. The Syrian offensive has also engulfed many of the 12 military observation posts Turkey has in Idlib.
Rhami Dogan, the governor of Turkey's Hatay province bordering Syria's Idlib region, said 32 wounded troops were being treated in hospitals. Turkey has had 54 soldiers killed in Idlib since the beginning of February.
Russia Foreign Minister Sergey Lavrov offered condolences to Turkey on Friday, saying "such tragedies" can be averted.
President Vladimir Putin and Turkish President Recep Tayyip Erdogan spoke by phone on Friday to discuss the crisis and both "expressed serious concern" over the escalation, the Kremlin said.
In a statement, UN Secretary-General Antonio Guterres expressed "grave concern" of an escalation of violence and called for an immediate ceasefire. He said "the risk of even greater escalation grows by the hour" without urgent action.
As fighting raged, the United Nations said it was having "catastrophic" humanitarian consequences, with at least 134 civilians, including 44 children, killed in February, and schools and hospitals destroyed.
Seven children were among 11 people killed when an air strike hit a school in northern Idlib on Tuesday, according to the UN.
Through his spokesman, NATO Secretary General Jens Stoltenberg issued a statement condemning the "indiscriminate" air strikes by the Syrian regime and Russian forces. He urged de-escalation by all parties of "this dangerous situation".
NATO nations will meet on Friday to address the crisis.
Following the air attack, Erdogan held a two-hour emergency security meeting in Ankara that was attended by ministers and military officials.
Defence Minister Hulusi Akar and Turkish commanders directed operations in Syria at the Turkish border, state-owned Anadolu news agency said.
Syrian state news agency, SANA, carried a brief report saying Turkey acknowledged its forces were killed "in operations of the Syrian Arab Army against a terrorist organization", adding Syrian troops were repelling attacks by "terrorist groups backed by Turkey".
Turkey has sent thousands of troops and heavy military hardware into Syria and Erdogan has warned Turkey would launch a full-scale offensive to repel Syrian forces unless they pulled back from Turkish observation posts in the region.
Vladimir Dzhabarov, a senior Russian lawmaker, said on Friday any full-scale Turkish military operation in Idlib would end badly for Ankara, the Interfax news agency reported.
Erdogan's spokesman, Ibrahim Kalin, who plays a senior role in foreign affairs, spoke about the situation to US National Security Advisor Robert O'Brien.
"We stand by our NATO ally Turkey and continue to call for an immediate end to this despicable offensive by the Assad regime, Russia, and Iranian-backed forces," the US State Department said in a statement.
The Turkish army was retaliating with artillery fire at Syrian government positions in Syria.
"All known" Syrian government targets are under fire by Turkish air and land support units, Turkey's communications director Fahrettin Altun said on Friday, adding it will "respond in kind" to the deadly air strike.
Russia, meanwhile, deployed two warships equipped with Kalibr cruise missiles to the Mediterranean Sea towards the Syrian coast, the Interfax news agency cited Russia's Black Sea Fleet as saying on Friday.
Attacks on Turkish forces have caused severe tensions between the Syrian government's key ally, Russia, and Turkey, which backs certain opposition groups in Idlib.
Erdogan has previously pledged to launch a military operation to push back Syrian government forces if they did not retreat from a line of Turkish observation posts by the end of February.
Meanwhile, Turkish media quoted officials as saying Turkey's police, coastguard and border security officials had been ordered against trying to stop Syrian refugees from reaching Europe, in anticipation of their imminent arrival from Idlib.
"We have decided, effectively immediately, not to stop Syrian refugees from reaching Europe by land or sea," one official who requested anonymity told Reuters news agency. "All refugees, including Syrians, are now welcome to cross into the European Union."
The threat to open the way for refugees to Europe would, if executed, reverse a pledge Turkey made to the European Union in 2016 and could quickly draw Western powers into the standoff over Idlib and stalled negotiations between Ankara and Moscow.
The burden of hosting refugees "is too heavy for any single country to carry", the official said.
Nearly 300 migrants arrived in Edirne province on the border with Greece in a bid to go to Europe, the private DHA news agency reported.
The group included Syrians, Iranians, Iraqis, Moroccans and Pakistanis, who told the agency they had come to the border after hearing the news about the killing of the Turkish soldiers.
Another group of migrants arrived at the coast of Ayvacik in Canakkale, western Turkey, and wanted to go to Lesbos by boat after reading reports of an "open-door policy", DHA reported.
The agency published images of people carrying their belongings, walking in the dead of night in Edirne and Canakkale.
Some 950,0000 civilians have fled the government offensive this year.
Turkey already hosts more than 3.6 million Syrian refugees and fears a new influx of hundreds of thousands of others, said Al Jazeera's Hashem Ahelbarra, reporting from the Turkish-Syrian border.
"In the coming days, [it is likely] to see Turkey take an aggressive role and ask the European Union and NATO, in particular, to take a very strong stance when it comes to what is happening now in Idlib," he said.
"Turkey feels that it is fighting this fight on its own, while it considers what it is doing as an attempt to put an end to the humanitarian [crisis in Idlib]."
The fast-moving events came as Turkey-backed Syrian opposition fighters retook a strategic northwestern town from government forces on Thursday, opposition activists said, cutting a key highway just days after the government reopened it for the first time since 2012.
Despite losing the town of Saraqeb, Syrian President Bashar al-Assad's forces made major gains to the south. Al-Assad now controls almost the entire southern part of Idlib province after capturing more than 20 villages on Thursday, state media and opposition activists said.