Reuters Italian media said a truck carrying cars collided on a bridge with another tanker truck containing inflammable materials.
The explosion caused a bridge to partially collapse.
Italian news agencies have reported that multiple injuries were caused by flying glass from broken windows.
They wrote: "tanker explosion: extinguished the flames, in progress the cooling operations".
More than a dozen people were seriously injured, local media said, including police officers and carabinieri (military police).
Police say the incident took place on the motorway close to the airport.
Fire raging on the motorway outside Bologna
Thick black smoke was seen rising up in the air from miles away from the site of the blast. Dashcam footage and photos of the explosion have gone viral. Aerial photos showed a gaping hole left in the raised highway.
The accident closed down a key section of a major north-south highway that is heavily used year-round, but especially as Italy heads into next week's peak summer holiday travel period.
A fuel tanker collided with another truck carrying vehicles on the A14 highway near the airport, sparking a fireball and plume of smoke was visible for kilometres.
Firefighters working on the motorway after the accident.
Italian police posted a video showing the damage down to the bridge after the blast, showing a crater in the road.