The former British prime minister also warned of further turmoil with the euro
The Brexit vote was part of a wider "movement of unhappiness" in the West that demands a "course correction" by political leaders, David Cameron has warned.
The former British prime minister also highlighted the election of Donald Trump in the US and the referendum turmoil in Italy as evidence of the need to reach out to people who felt left behind.
Giving a speech in America on the events of 2016, Mr Cameron - who quit Downing Street following the outcome of the EU referendum in June - said "populism" had cost him his job.
But he defended his decision to hold the referendum, arguing the issue of Europe had "poisoned" British politics for four decades.
Taking questions from students at DePauw University in Indiana, Mr Cameron said: "So far these three events - the Brexit referendum, the election of President Trump, the referendum in Italy - I'm sure people are going to write about this movement of unhappiness and concern about the state of the world.
"I think you could see that in the British vote ... was a mixture of economics and cultural arguments, I think your situation [in the US] was quite similar, I think in Italy it's more connected with the euro.
"But ultimately, how 2016 goes down in history will depend on what political leaders do next. That's why I have tried to make a very clear argument which is that if they put their heads in the sand and say, 'well this will pass and we just carry on the way we are', then 2016 will be seen as a real watershed.
"But if, as I believe will happen, that our democracies are flexible enough and our leaders are aware enough, they will correct - course correct as I put it - the problems that they face.
"So you will see a greater emphasis on trying to help those who are left behind."
He pointed to a higher minimum wage and tax cuts for low-income workers as measures aimed at meeting that need.
Mr Cameron added: "I think if that response is right, 2016 will be seen as a moment of course correction rather than a moment of fundamental change. But if leaders don't take that approach - perhaps particularly in Europe - then it could go down as something quite different."
Mr Cameron also warned of further turmoil with the euro.
He said: "I think there does come a time when some countries will think we've had no growth for too long, and they will start to question the way this currency works and whether it's working in their interests."
The former prime minister's speaking engagement came as it was revealed George Osborne, the former chancellor, had earned more than £500,000 (around €600,000) from lectures and appearances since losing his job when Theresa May took over at 10 Downing Street.