The measure - which is not the first time that Italy's economic capital has banned driving within city limits - has been met with scepticism by some, with the regional counsellor for the environment, Raffaele Cattaneo, calling it "demagogy with a green sauce".
Milan's mayor, Beppe Sala, himself acknowledged the measure would not solve the city's pollution problem in the long-term, pointing a finger at polluting heating systems and cars.
Smog has been a recurring problem in Italy's industrial north, especially in Milan and neighbouring Turin, and previous authorities have often turned to banning cars.
A European Court of Auditors report published in September 2018 found that cars were a "major source of urban air pollution" in Milan, and said the most effective measures would be to limit their use.
On Sunday, residents of Italy's economic capital and tourists will have to get around via bike, electric scooter or public transport from 10:00 (9:00 GMT) to 18:00.
Some streets will remain open to traffic, in particular to allow access to the San Sir Stadium, where AC Milan meets Hellas Verona in the afternoon.
Earlier this month, Sala proposed that smoking be banned at bus and tram stops, part of a wider plan to ban smoking outright in open spaces by 2030. It will be submitted to the city council in March.
Cattaneo said cigarette smoke constitutes a mere 1.9 percent of environmental emissions.
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