Italian authorities said 19 cities, including Rome, Milan, Venice and Naples, were under the highest alert level on Saturday, with the number expected to rise to 25 by Monday.
Temperatures reached around 35 degrees Celsius across large parts of the country.
Officials warned that the extreme heat could affect not only vulnerable groups but also healthy adults.
Residents have been advised to avoid direct sunlight between 11am and 6pm, stay indoors where possible and drink plenty of water to reduce the risk of heat-related illness.
Unlike previous heat warnings, which mainly focused on older people and those with existing health conditions, authorities said the current conditions could also have serious effects on otherwise healthy and active individuals.
The heatwave is being driven by a strong high-pressure system moving north from North Africa, bringing exceptionally hot conditions across the Mediterranean region.
The alert comes as several European countries continue to battle large wildfires fuelled by prolonged heatwaves and dry weather.
According to data from the Copernicus Climate Change Service, Europe is warming faster than any other continent, at roughly twice the global average rate.
Scientists say rising temperatures are increasing the risk of more frequent and intense heatwaves, prolonged droughts and destructive wildfires across the continent.
