The law is a flagship proposal of the co-governing League of Deputy Prime Minister Matteo Salvini, who has seen his popularity slide and is keen to regain it in the party's traditional northern heartlands.
The bill, which will also need approval from the lower-house Chamber, was passed by a 110-64 vote. It enables regions to claim broader powers on key public services such as health and education, and have a bigger say on how taxes are spent.
"It is an important step towards a more modern and efficient country," Salvini said, hailing the Senate's approval.
The reform faces strong criticism from opposition parties, which argue that it risks further widening the wealth gap between the north and the south, an issue that has dogged Italy since the country was unified in 1861.
Italy's Calabria is one of the poorest regions across the European Union, with gross domestic product per capita of only 56% of the EU average, according to 2021 data from EU statistics agency Eurostat.
By contrast, GDP per capita in the northern alpine province of Bolzano stands at 151% of the EU average.
Right-wing ruled Lombardy and Veneto, as well as left-leaning Emilia-Romagna, are among the northern regions expected to make use of the new law, once it is approved, to obtain more autonomy from Rome.
Under the legislation, once a region applies for more autonomy, a negotiation would start with the central government on the extent of powers that could be devolved.
Prime Minister Giorgia Meloni's rightist coalition is pushing through the regional autonomy bill as part of a wider overhaul of the Italian state, including constitutional reform plans for a directly-elected head of government.
(Reporting by Angelo Amante and Alvise Armellini, editing by Mark Heinrich)
