"All of Fort McMurray is under a mandatory evacuation order," Alberta emergency services announced, after previously indicating that the northern edge of the fire was "growing rapidly."
The airport was still open.
"Be patient, drive safely and please give way to emergency vehicles," an evacuation notice read.
Gas stations exploded and several homes have already been burnt down, including one of the town's many motor home parks, according to local media.
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Authorities urged residents to head toward evacuation centers as the city reeled from what Alberta premier Rachel Notley called the province's largest evacuation.
Long lines of cars headed north via the main highway of the city, while flames ravaged the embankment on the side of the road. Police closed the southward lanes.
"Seek medical attention if you experience breathing difficulties," emergency services said.
The fire, which was contained until Monday south of Fort McMurray, was pushed toward the city by winds and quickly reached homes, helped by a drought in Alberta.
"I know that it's a very scary time," Notley told a press conference. "I know it's a very, very stressful time for people to have to leave their homes under these conditions."
"My thoughts are with people affected by the fire in Fort McMurray tonight. Stay safe and remember to follow evacuation orders," he tweeted.
"We stand ready to help."
A more limited alert earlier saw authorities evacuate 30,000 people.
The province saw record temperatures of nearly 30 degrees Celsius yesterday.
On Monday, some 500 people were evacuated under an initial alert due to smoke from the wildfire.