The magnitude-six quake struck in the middle of the night, about 35km (22 miles) north of the city of Bologna.
The four victims were killed by falling masonry. Italian media report two more quake-related deaths.
The tremor caused "significant damage to the cultural heritage" of Emilia Romagna region, the government said.
The culture ministry said firefighters and civil protection workers were now examining damaged historic buildings.
It was the worst tremor to hit the country since the L'Aquila quake killed nearly 300 people in central Italy in 2009.
The earthquake struck at a relatively shallow depth of 10km just after 04:00 local time (02:00 GMT).
It was felt across a large swathe of northern Italy, including the cities of Bologna, Ferrara, Verona and Mantua and as far away as Milan and Venice.
The tremor forced many terrified residents into the streets.
Two people were killed in Sant'Agostino when a ceramics factory collapsed.
The mother of one of the victims told local media that "he wasn't supposed to be there. He changed shifts with a friend".
Another person - believed to be a Moroccan national - was killed in Ponte Rodoni do Bondeno.
In Tecopress di Dosso, one worker died when the roof of foundry collapsed, Rai News24 reports.
Local media also say a woman died near Bologna, with reports suggesting that she may have had a heart attack. Another victim was an elderly woman in Sant-Agostino.
About 50 people were injured - but none seriously, reports say.
Aftershocks were reported soon after the quake.
"I was woken at around 4am by the quake, it was strong and lasted up to a minute, maybe more," Frankie Thompson, a UK travel journalist in Bologna, said.
"Church bells were set off spontaneously... followed by an eerie silence. Small aftershocks kept coming and going until maybe 5:50am when a stronger tremor shook us again but not as long and dramatic as the first," she added.
Britain's David Trew, who is staying in a hotel in Ferrara, told said: "I was sound asleep when the tremors started. I was having quite a vivid dream, and the first few seconds of the quake became part of the dream.
"As I began to wake up it took me a few seconds to realise that it was actually happening for real. I fumbled around in the darkness, now very scared. The room was shaking violently, plaster was dropping off the ceiling into my hair and all over the floor."
One local resident told Ansa: "I heard a big bang and I ran on the terrace, I was afraid of falling."
TV footage later showed people inspecting damaged houses, offices and historic buildings. Parts of a castle in Finale Emilia collapsed.
Emergency officials ordered the evacuation of patients from hospitals as a precautionary measure.
Northern Italy is frequently rocked by minor earthquake, but the country is well-prepared to deal with them.
In January, a 5.3-magnitude quake hit northern Italy but caused no injuries.
Source: BBC News
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