The referendum was Cameron delivering on an election promise — but the premier had forcefully campaigned for Britain to remain in the EU.
The results served as an indictment of Britain's government and immediately sparked speculation about Cameron's political future.
Cameron said early Friday that the British people had spoken — and "their will must be respected."
With markets in freefall after the result, Cameron attempted to reassure anxious investors that the British economy was "fundamentally strong" and that any trade or travel changes would not be immediate.
He said outside of Downing Street that he was "very proud" and "honored" to have led the country for six years — but that Britain now "must prepare for a negotiation" with the European Union, one that "will require strong, determined and committed leadership."
"I do not think it would be right for me to be the captain that steers our country to its next destination," he told reporters outside his Downing Street office.
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David Cameron (UPDATED 5/8)
David Cameron (UPDATED 5/8)
Britain's Prime Minister David Cameron returns to 10 Downing Street in London after attending a VE Day service at the Cenotaph, Friday, May 8, 2015. Cameron's Conservative Party swept to power Friday in Britain's Parliamentary elections winning an unexpected majority. (AP Photo/Kirsty Wigglesworth)
Britain's Prime Minister David Cameron and his wife Samantha smile from the steps of 10 Downing Street in London Friday, May 8, 2015, after meeting with Britain's Queen Elizabeth II in a traditional formality, where he informed her that he has enough support to form a government. Cameron's Conservative Party swept to power Friday in Britain's Parliamentary General Elections, winning an unexpected majority. (AP Photo/Kirsty Wigglesworth)
LONDON, UNITED KINGDOM - MAY 08: (L-R) Labour leader Ed Miliband, Liberal Democrat leader Nick Clegg and Prime Minister David Cameron attend a tribute at the Cenotaph to begin three days of national commemorations to mark the 70th anniversary of VE Day May 8, 2015 in London, United Kingdom. Both Miliband and Clegg said they will resign their posts as party leaders after they were soundly beaten by Cameron and his Conservative Party in yesterday's general election. (Photo by Chip Somodevilla/Getty Images)
Britain's Prime Minister and Leader of the Conservative Party David Cameron and his wife Samantha are applauded by staff upon entering 10 Downing Street in London on May 8, 2015, after visiting Queen Elizabeth II, a day after the British general election. British Prime Minister David Cameron's Conservative party on Friday won a majority in the House of Commons in the general election, results showed. AFP PHOTO / POOL / STEFAN ROUSSEAU (Photo credit should read STEFAN ROUSSEAU/AFP/Getty Images)
British Prime Minister David Cameron speaks during a United Nations Security Council meeting, Wednesday, Sept. 24, 2014, at at U.N. headquarters. Members of the Security Council were expected to adopt a resolution that would require all countries to prevent the recruitment and transport of would-be foreign fighters preparing to join terrorist groups such as the Islamic State group. (AP Photo/Julie Jacobson)
United Kingdom's Prime Minister David Cameron addresses the 69th session of the United Nations General Assembly, Wednesday, Sept. 24, 2014, at U.N. headquarters. (AP Photo/John Minchillo)
British Prime Minister David Cameron attends a meeting of the United Nations Security Council regarding the threat of foreign terrorist fighters during the 69th session of the U.N. General Assembly at U.N. headquarters, Wednesday, Sept. 24, 2014. (AP Photo/Jason DeCrow)
British Prime Minister David Cameron addresses the 69th session of the United Nations General Assembly Wednesday, Sept. 24, 2014, at the United Nations headquarters. (AP Photo/Frank Franklin II)
British Prime Minister David Cameron meets with Iranian President Hassan Rouhani at the UN during the 69th Session of the UN General Assembly, Wednesday, Sept. 24, 2014. (AP Photo/Timothy A. Clary, Pool)
President Barack Obama speaks at the UN Security Council summit on foreign terrorist, Wednesday, Sept. 24, 2014, at UN headquarters. Front row, from left are, British Prime Minister David Cameron, UN Secretary General Ban Ki-moon and the president. Behind are Secretary of State John Kerry and US Ambassador to the UN Samantha Power. (AP Photo/Pablo Martinez Monsivais)
British Prime Minister David Cameron greets President Paul Kagame of Rwanda before a meeting of the United Nations Security Council regarding the threat of foreign terrorist fighters during the 69th session of the U.N. General Assembly at U.N. headquarters, Wednesday, Sept. 24, 2014. (AP Photo/Jason DeCrow)
British Prime Minister David Cameron speaks during a high-level meeting at the Ford Foundation on post-2015 anti-poverty goals, Wednesday, Sept. 24, 2014, in New York. (AP Photo/John Minchillo, Pool)
British Prime Minister David Cameron speaks during the United Nation Climate Summit at U.N. headquarters, Tuesday, Sept. 23, 2014. (AP Photo/Seth Wenig)
British Prime Minister David Cameron leaves after giving a statement to the media about Scotland's referendum results, outside his official residence at 10 Downing Street in central London, Friday, Sept. 19, 2014. Scottish voters have rejected independence, deciding to remain part of the United Kingdom after a historic referendum that shook the country to its core. The decision prevented a rupture of a 307-year union with England, bringing a huge sigh of relief to the British political establishment. (AP Photo/Lefteris Pitarakis)
NEW YORK, NY - SEPTEMBER 24: British Prime Minister David Cameron (L) meets with Iranian President Hassan Rouhani at the Unityed Nations during the 69th Session of the UN General Assembly September 24, 2014 in New York City. World leaders, activists and protesters have converged on New York City for the annual UN event that brings together the nations for a week of meetings and conferences. This year's General Assembly has highlighted the problem of global warming and how countries need to strive to reduce greenhouse gas emissions. (Photo by Timothy A. Clary-Pool/Getty Images)
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A clearly emotional Cameron said he would resign as prime minister by the fall, adding it was "not a decision I've taken lightly."
The news hit as Londoners were racing to work, with many glued to their cellphones as the headlines were alerted.
"I'm happy to see him go," said legal assistant Colette, 42.
She told NBC News that she hadn't voted for Cameron — and had cast a ballot in favor of leaving the EU.
"I thought there need to be some big changes," said Colette, who would only give her first name. She said she was "shocked" that the "Leave" camp won.
"It is gonna be a little bit crazy for a while but I think it's going to even out," she added.