There are less than two weeks to go before the Italian public have their say on a set of reforms which Renzi argues will cut down on bureaucracy and politicians' salaries, but which opponents claim would leave too much power in the hands of the prime minister.
And the outlook is far from rosy for the Prime Minister.
Polls are predicting his defeat, and he is struggling to counter criticism from his opponents and convince the public a vote for his reforms is not a vote for the 'establishment', while at the same time not stoking fears of chaos in the event of a 'No' victory.
A blackout on opinion polls began on Saturday, so we won't have any further insight into the views of the electorate until the final result is revealed on December 4th.
The last polls, published on Friday, showed the 'No' camp extending their lead, generally by around five points but with a ten-point lead reported by Ipsos for the Corriere della Sera.
They also showed a large proportion of Italians remained undecided. Around a third of voters said they hadn't yet made up their minds, with some polls showing that as many as one in four were unclear about the content of the referendum.
Renzi has repeatedly said he expects a "silent majority" to vote for him, and that he has "a lot of trust" in the electorate. What's more, levels of trust in polling are low after inaccurate predictions of the UK's referendum and the US elections - but it's clear that Renzi is facing more of a battle than he anticipated.
Tensions between the 'Yes' and 'No' camps heated up over the weekend, as Five Star Movement leader Beppe Grillo published a video accusing the 'Yes' camp of being "serial killers of our children's futures".
Renzi responded by brushing off the comments in a live Facebook chat, saying that former comedian Grillo was a "communications expert" and warning voters: "Don't fall for it". He said that the comments merely proved the Five Star Movement was "in trouble" over a series of scandals which have embroiled the party.
Acutely aware of the current trend towards 'anti-establishment' votes, Renzi has in recent weeks sought to frame his reforms as a vote for change, and to equate his opponents with the stagnant status quo.
In an interview with Italian daily Quotidiano, Renzi said it was "obvious" that the 'anti-establishment' Five Star Movement now represented the political elite. He pointed to accusations that the Movement had engaged in electoral fraud, and a rent scandal uncovered by L'Espresso magazine, which claimed that party members had paid for rent using Senate funds.
On the other hand, Renzi said that a vote for his proposed changes would be a vote "against the current system".
He's having a hard time convincing people of this however, particularly in the south of the country, where support for his government and reforms is weakest, and where residents suffer from above-average unemployment and poverty.
The reforms would see regional governments lose some of their power, with a lot of re-centralization of decision-making; a policy likely to be unpopular with those southern voters who already feel marginalized.
To complicate matters further, Renzi is not only trying to convince the public that his reforms would bring about positive change for Italy, but is also trying to allay fears across Europe that a loss would send the EU into turmoil.
On Monday, Britain's Financial Times said that Italy's referendum "could accelerate the path towards euro exit", if the reforms fail to pass - a worry several other commentators have raised. The paper argued that a loss for Renzi would lead to political chaos - the PM recently renewed an early promise to resign if his reforms didn't go through - and Europe could find itself facing "an immediate threat of disintegration".
Renzi immediately sought to play down the potential effect on the European economy and EU, telling Quotidiano on Monday that the referendum was "not about the euro" but rather "about the many euros which are spent on politicians".
But while Renzi is seeking to calm the fear of major repercussions in the event of a 'No' vote, and has said he doesn't anticipate "major disasters" if he loses, he is still clear that he believes a 'Yes' victory would be the best thing for Italy's economy.
Italian Finance Minister Pier Carlo Padoan has been clear that there would be repercussions if the 'No' camp triumphs on December 4th. He has said that a 'Yes' vote would provide much-needed stability to the Italian economy, and that on a global level it could be an antidote to the uncertainty caused by Brexit and Donald Trump's election.
Renzi has said that while global markets would probably not be significantly affected by Italy's referendum, a 'No' victory would likely have an effect on domestic economy, and would hit the poorest families hardest.