The Italian news agency ANSA reported the explosion was caused by an accident involving a truck that was transporting flammable substances, which exploded upon impact.
Two people have been killed and at least 60 injured, Italian outlet La Stampa reports.
Videos of the blast site showed flames shooting up in the air, followed by a thick cloud of black smoke.
Police said: "Due to an accident on the highway, an explosion occurred resulting in a fire at Via Marco Emilio Lepido".
Video gran of fireball emanating after the explosion near Italy Airport.
Fire raging on the motorway outside Bologna
The explosion also engulfed a nearby Peugeot auto dealership and other shops, The Local reported.
Italian media reports that some people were injured by glass flying from windows shattered by the force of the explosion.
The windows of many houses in the area are reported to have burst.
Firefighters have since put out the blaze, a spokesman said, adding that efforts were under way to ascertain the cause of the explosion and the precise number of victims. Authorities closed the highway in both directions as firefighters work to put out the fire. The interchange connects two major highways linking northern Italy with the Adriatic coast, a popular destination as Italy heads into its major summer holiday next week.
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