Senators backed Prime Minister Guiseppe Conte's new government with 169 in favour and 133 against.
Italy's new coalition government can get to work after senators gave it the green light on Tuesday evening.
They backed the new alliance between Five Star Movement (M5S) and the Democratic Party (PD) by 169 votes to 133.
It was the second of two mandatory votes of confidence to confirm the government, which will be headed by Prime Minister Guiseppe Conte.
Conte said the vote signalled "a new beginning for Italy, a reforming season of revival and hope".
"The constitution and respect for our institutions will be our compass, and the interests of Italians our goal," he added.
MPs in the lower house of parliament gave their own seal of approval on Monday evening with a 343-263 ballot in favour after Conte promised the new government "will be mild-mannered" in a thinly-veiled rebuke to his former colleague Matteo Salvini.
Conte also underlined that the country would seek to improve relations with Brussels to work towards building "a more solid, more inclusive Europe" and to change the bloc's economic governance and migration policies.
"We cannot in the coming months waste our time with disputes and clashes," Conte told lawmakers in parliament. "We must be sober in our words and active in our deeds."
"The language of this government will be mild-mannered because we understand that our actions will not be judged by the arrogance of our words," he added.
Conte was first appointed Prime Minister in June 2018 as a compromise pick between the populist M5S and the far-right League parties forming the ruling coalition. But the government was soon bogged down by bickering with League leader and Interior Minister Matteo Salvini casting a large shadow over his M5S counterpart, Luigi di Maio.
But Salvini, boosted by solid opinion polls and European elections in which the League scored much higher than the M5S, pulled the plug on the coalition in early August in the hope of triggering elections that would allow the League to rule alone.
But the M5S scuppered his plans by negotiating a coalition deal with the centre-left PD party.
Reacting on Twitter after the Senate vote of confidence, Salvini described September 10 as the "national day of betrayal".
The country's new cabinet has been filled with moderate and pro-Europe ministers.
The crucial economy ministry was given to PD's Roberto Gualtieri, the chairman of the European Parliament's Committee on Economic and Monetary Affairs, while independent Luciana Lamorgese will replace Salvini, at the interior ministry.
Lamorgese, the first woman to lead the Milan prefecture, is a veteran at the interior ministry, which she first joined in 1979. Over the past decade, she has primarily worked on migration and the integration of refugees and migrants.
Conte will meet with European Commission President Jean-Claude Juncker in Brussels on Wednesday afternoon, a spokesperson for the Commission announced on Monday.