As secretary of the PD, the brash 38-year-old will likely have to tone down the rhetoric calling for the ouster of the party's top brass that has helped make him one of the country's most popular political figures in the past two years.
Data from two-thirds of the 9,000 polling booths showed Renzi took 68% of the vote in a three-way race to lead the largest party in parliament and in the ruling coalition.
About two-and-a-half million people cast a primary ballot, Renzi said, which was far more than envisioned and is a clear sign voters want to renew the party founded six years ago by merging elements of the former communist party and left-leaning centrists.
Renzi will not join the government, but is likely to lead the PD into the next election as its candidate for prime minister. Primary rivals Gianni Cuperlo, a former communist, and the web-savvy Pippo Civati acknowledged Renzi's leadership in their concession speeches.
"This is the end of group of party leaders, not of the left," Renzi told his supporters in a victory speech in Florence, after promising to unify the party. "Now it's up to a new generation, my friends. It's our turn to drive the car."
For his charisma and goal to remodel Italy's left, the Florence mayor is sometimes compared to Britain's Tony Blair, but his direct speaking style and media savvy also draw comparisons to the 77-year-old centre-right leader Silvio Berlusconi
Fill the void
With the centre right in disarray after former prime minister Berlusconi's tax-fraud conviction and a subsequent party split, Renzi has the opportunity to recast the PD to attract some disillusioned right-wing voters.
Polls have shown Renzi is popular even among centre-right voters. Lower taxes - a warhorse for Berlusconi for two decades - are a central part of his programme, as are promises to change the electoral law, overhaul labour rules, and eliminate the privileges of the political class.
Two weeks ago, Renzi said that if he won the primary he would call on the government to step up its reform efforts or else declare it "finished". But few, even among his loyalists in parliament, say it would be to Renzi's advantage to seek elections now, as he needs time to unify the party behind him.
For his part, Letta has insisted that the primary will make his government stronger, and Renzi and the premier will meet as early as Monday, government and party sources told Reuters.
"The government will last until at least 2015, if not longer," one source close to Renzi told Reuters.
"With the new secretary, Matteo Renzi, we will work together with team spirit that will be productive for the country and the centre left," Letta said in a statement after Renzi's victory.
Apart from many still-pending economic reforms, the government faces an unpredictable new challenge following last week's move by the Constitutional Court to reject parts of the current voting law.
The ruling leaves Italy with a proportional voting structure that would virtually guarantee short-lived coalitions and worsen the stalemate that has afflicted the system in recent years. It will take careful negotiations to build support, also outside the PD, for new election rules.
Though Renzi appears to have won a decisive victory with the general public, inside the party he will still need to build support among those suspicious of his unabashed ambition, his centrist past and his forceful and - for the left - unorthodox media presence.
Earlier this year, Renzi went on a TV talent show popular with teenagers and broadcast by Berlusconi's network. Dressed in a black leather jacket, at one point he gave a thumbs-up that earned him the nickname "Fonzie", a reference to the laid-back hero of the U.S. sitcom "Happy Days".
Renzi embraced it, posing in a leather jacket for a magazine and explaining: "I want everyone to hear my message".