The Italian news agency ANSA reported the truck was carrying liquefied petroleum gas but officials said they could not confirm that.
A police video showed the tanker failing to break and plowing into the rear of a truck stopped in traffic, with flames exploding on impact. Another truck appeared to hit the tanker from behind. After an unspecified time lapse, during which the highway was cleared of most other vehicles, there was a second, enormous explosion, which spanned eight lanes of the highway and beyond.
Flames shot up into the air, followed by a thick black cloud of smoke. Aerial photos showed a gaping hole left in the raised highway.
The Italian television Sky TG24 said flames from the explosion set off secondary blasts in a new car lot below.
A woman living a kilometer from the blast site said many residents had to leave due to the black smoke.
"I was in the house and I heard a huge bang and screams from the window. I saw a huge plume of smoke," Crisina Felicani told Sky TG24. "There was panic in the neighborhood, because it wasn't clear what happened."
Several hours after the explosion, firefighters said they had extinguished the flames, ANSA reported.
Authorities said the accident closed down a major interchange connecting highways linking northern Italy with the Adriatic coast, a popular destination as Italy heads into next week's peak summer holiday travel period.
Italy's infrastructure and transport minister, Danilo Toninelli, said authorities were working to ensure that traffic would be able to move smoothly "on such a critical stretch."
In a separate accident in the southern Italian region of Puglia, 12 farm workers were killed Monday when the van they were traveling in collided with a truck and overturned, ANSA reported.
The accident was similar to one on Saturday, when a truck laden with tomatoes crashed into a white van and four migrants died.