The former prime minister announced he was stepping down as MP for Witney with immediate effect.
It comes nearly three months after he resigned as the country's leader in June following the UK's vote to leave the EU in a national referendum.
Mr Cameron told ITV News that he had thought "long and hard" over his choice but had ultimately decided that he would be a "distraction" from the work of government.
Video report by ITV News Deputy Political Editor Chris Ship
Mr Cameron said that he had informed Theresa May of his decision this afternoon and she was "very understanding".
He denied that his last political legacy would be as the man who took Britain out the EU.
"I’m sure I will remembered for keeping that pledge to hold a referendum when many people thought that promise would never be kept," he said, adding that he had also overseen social reform and sought to modernise the party.
His resignation will trigger a by-election.
"Obviously I’m going to have to start to build a life outside Westminster," he said as he announced his decision in Witney.
"I'm only 49 and I hope I can still contribute in terms of public service and contribute to our country."
He added that he will continue to live in Witney and that it had been a "honour" to serve the area.
Mr Cameron also released a formal statement confirming his decision to stand down.