It was a move that backfired spectacularly and led to the dramatic announcement that he'll quit as Britain's prime minister in the aftermath of the Brexit vote -- an era-defining moment that will no doubt lead to him being remembered for generations to come as the man who took the country out of the European Union.
For a man who told members of the Conservative Party to stop "banging on" about Europe in his first conference speech as leader, it is perhaps fitting that his reign comes to end with such symmetry.
Outside 10 Downing Street Friday, Cameron, who had defiantly championed the cause of the Remain campaign, conceded that his position had become untenable after a night of drama.
Though Cameron said he would remain in charge until a new leader is appointed in early October, he pledged to try to "steady the ship" over the coming months before handing over responsibility.
It's a huge blow to Cameron, who led the Conservative Party to victory in the 2015 general election and saw off the threat of Scottish independence a year before that.
But his decision to attempt to solve party infighting and see off the threat of the United Kingdom Independence Party by offering a referendum on membership of the EU if he won the general election has proved fatal to his reign.
Cameron's name will no doubt be cast by some alongside the likes of Neville Chamberlain and Anthony Eden, former prime ministers whose careers were defined by failure.
Cameron had been regarded as a lucky politician by some of his closest colleagues but that luck ran out as the "Leave" campaign won 51.9% of the vote to win by 1,269.501 votes, with turnout at 72%
He'll now be left to watch on as rivals make a claim for his job, with Boris Johnson, the former mayor of London, the current favorite.
Clearly emotional, Cameron, with his wife Samantha by his side, ran through his achievements, including the introduction of gay marriage and progress with the country's economy.
"I fought this campaign in the only way I know how, which is to say directly and passionately, what I think and feel -- head, heart and soul.
"I held nothing back, I was absolutely clear about my belief that Britain is stronger, safer and better off inside the European Union and I made clear the referendum was about this and this alone -- not the future of any single politician including myself.
"But the British people have made a very clear decision to take a different path and as such I think the country requires fresh leadership to take it in this direction.
"I will do everything I can as prime minister to steady the ship over the coming weeks and months but I do not think it would be right for me to try to be the captain that steers our country to its next destination.
"This is not a decision I've taken lightly but I do believe it's in the national interest to have a period of stability and then the new leadership required."
But all of those points will be washed away by the enormity of this result -- a result that has changed the landscape of British politics forever.
Cameron's undoing was that he believed the constant infighting within the Conservative Party over Europe had to be resolved -- but the calling of a referendum was an unnecessary gamble.
He attempted to use the economy to persuade voters that remaining in Europe would be best for Britain -- but "Project Fear"
as it was dubbed by his opponent, failed to resonate with a divided country.
He resignation was perhaps inevitable -- a man who said that leaving the EU would be like "putting a bomb under our economy" was never going to be able to negotiate the country's exit.
In the end, Cameron's gamble, one that he had been warned against, failed to come off, as CNN's Max Foster summed up from Downing Street.
"We thought he would reassure the markets but obviously the pressure was so high that he had to come out with another solution and he fell on his sword. An extraordinary day here.
"What this country doesn't need right now is more political instability on top of the market turmoil," Foster said.