Manchester had the strongest Remain vote in the North West - but the majority of districts in the area voted to leave the European Union.
In Greater Manchester, Manchester voted 60.4% to stay, followed by Trafford at 57.7% and Stockport at 52.3%.
Wigan, Tameside and Oldham at 63.9%, 61.1% and 60.9% respectively topped the Leave votes.
Interim mayor Tony Lloyd said it was not the result they "hoped for" and work to analyse the impact would begin.
Mr Lloyd, who is also police and crime commissioner for Greater Manchester, said: "It is no secret that this is not the result Greater Manchester leaders had hoped for but Greater Manchester is a vibrant and resilient place.
"Our city-region will continue to transform and grow, driven by the talent and determination of our people.
"The Greater Manchester Combined Authority will now begin work to analyse the effect of our exit from the EU and work to ensure the best possible future for our city-region."
The Electoral Commission's chief counting officer, Jenny Watson, announced the referendum result at Manchester Town Hall after all 382 local totals had been certified and declared.
Lucy Powell, Labour MP for Manchester Central, tweeted: "What a devastating outcome for jobs and the economy. We now need to do all we can to get the best for Britain."
Wigan MP for Labour, Lisa Nandy, said: "I think what we need to do is not to panic and to try to think about how to move forward as a country.
"We need to listen to concerns that have been raised on both sides."
Labour Leave supporter Graham Stringer, MP for Blackley and Broughton, said: "We've [the UK] got to negotiate a good deal - the countries in the EU are still our friends.
"We have to have good relations with them. So it's going to be a fascinating and interesting time. But being a self-governing country is not uncharted waters."
Kevin Fitzpatrick, Radio Manchester Political Reporter
It was in the more deprived parts of northern Greater Manchester where most voters plumped for Brexit.
In Rochdale, Oldham, Tameside and Wigan more than 60% voted to leave - a sign of the long-simmering frustration over immigration and its perceived impact on jobs.
Manchester, Stockport and Trafford came in for Remain, but with an overall average of about 55% Greater Manchester's Leave voters made a big contribution to the national result.
Greater Manchester Chamber of Commerce said the government must "deliver changes with minimum detriment to the economy and businesses".
Chief executive Clive Memmott said: "The focus in the first instance must be to limit uncertainty and instability, and send clear messages as to the path ahead.
"Government has a clear mandate for change from voters, but should take as much time as needed to deliver these changes."
The owner of a clothing firm that exports its goods globally and employs about 20 different nationalities described the result as "unsettling".
James Eden, who owns Salford-based Private White VC, said: "I'm unsettled as a business owner, I'm unsettled as a British national, I'm also unsettled for my amazing workforce.
"I think it's important for us not to knee jerk because in the medium and long term I'm inclined to say things will work themselves out.
"In the short term there is going to be a bump in the road."