Liverpool, Wirral and Sefton voted to remain in the European Union - but every other district in the area voted to leave.
Liverpool voted 58.2% to stay, followed by Sefton at 51.9% and Wirral at 51.7%.
St Helens and Halton topped the leave votes at 58% and 57.4% followed by Warrington, Knowsley and Cheshire West and Chester at 54.3%, 51.6%, 50.7%.
Frank Field, MP for Birkenhead and the only Merseyside MP to vote leave, said it was a "clear revolt".
He tweeted: "This result is the first clear revolt against globalisation and its undermining of working-class living standards."
He said the government now "needs to be reformed" and the "major task" is to "reassure Europe that we want our negotiations to be successful for them, but also for Great Britain."
Mayor of Liverpool, Joe Anderson, said he thinks people voted to leave because they became fed up with cuts.
"It was David Cameron's failure to recognise those issues and the rise of UKIP when he called for the referendum.
"My leader, Jeremy Corbyn has been pointing out that most people's anger is around the austerity programme."
Paul Nuttal, North West MEP and deputy leader of UKIP, said he was looking forward to "making our country" one "that looks forward into the 21st Century".
"I'm looking forward to this country taking back control of its borders... its destiny... its own laws... its own money and making our country great again," he said.
Claire Hamilton, Radio Merseyside Political Reporter
Liverpool so often bucks the national trend, and here the level of European funding which has been allocated to the city over the past 20 years possibly swayed voters.
That funding's also gone to St Helens and Knowsley, which both voted to leave the EU but perhaps isn't so visible.
People we spoke to in St Helens said they felt Britain would be better off in the long run on its own.
But St Helens South MP Marie Rimmer says she's disappointed the town voted to leave and is furious with the Remain campaign.
She said they hadn't done enough to highlight to ordinary people in towns like St Helens what benefits the EU has brought.
She said the EU had saved the glass industry in St Helens in the 1980s, helped build the town's first hotel and re-trained miners who lost their jobs in the pits.
The government's focus was centred too much on the cities, she said, and Liverpool is perceived to have received the lion's share of EU funding when in reality "all of Merseyside has benefitted".
Labour MP for Wallasey, Angela Eagle, said the Brexit vote was "protest" from communities "under the most pressure".
She said many people appear to have directed discontent with a variety of issues in their communities at the EU.
"What the Leave campaign have done is give it a scapegoat - the European Union - as the cause of that pressure, whereas actually the cause of a lot of that pressure is cuts and conservative policies," she said.
There will be "a period of huge uncertainty" because of "all the things we're heavily reliant on in Merseyside," said Wirral Council leader Phil Davies, who backed the Remain campaign.
"For trade, we've got lots of European money tied up with some important initiatives. For example, we've got a £42m programme funded by European social funding for getting unemployed people back into work.
"I think there's huge uncertainty now about all of these moneys and all of these programmes going forward," he said.
Phil McCann, Cheshire Political Reporter
In parts of Cheshire the vote was just as split as it was nationwide - with 50.7% in Cheshire West voting to leave and 51.2% in Cheshire East.
But in more traditional working class Labour voting areas like Warrington and Halton the Leave vote was much more decisive.
Cheshire's farmers may now be wondering what this means for their subsidies and unpopular regulations, while the effect on housing developers looking to develop large areas of the countryside remains to be seen.