The municipal vote was the government's first test at the ballot box after the League and anti-establishment M5S took office on June 1 following months of political turmoil.
A total of 6.7 million Italians were eligible to vote on Sunday in 760 cities across the country, as well as two of Rome's 15 boroughs.
Most of the major cities up for grabs were represented by the centre-left and backed by the former ruling party Democratic Party (PD).
Early results showed the League-led right-wing coalition wresting control of the largest city in play, Sicily's Catania, as well as Vicenza in the northeast, from the centre-left.
However, the centre-left looked set to hold on to the northern city of Brescia and will head into run-off votes on June 24 against right-wing candidates in the Tuscany's Pisa and Siena.
The PD's losses follow the party's crushing result in March's parliamentary election, where it garnered just 23 per cent.
The right-wing coalition won the most votes with 37 per cent while the M5S became the country's biggest party with 33 per cent and, after nearly three months of horse-trading, joined forces with the League to form government.
However, early results showed the M5S suffered setbacks on Sunday, winning just 10 per cent of the vote in Pisa, and almost 13 per cent in Sicily's Messina.
The movement also failed to win either of the seats in Rome, where the party's Virginia Raggi has been mayor since 2016.