Vamplew, whose previous best cash was just $6,000, grabbed the £900,000 first-place prize while the four-time World Series of Poker bracelet winner took £545,000 for second.
“It’s going to take a while to sink in," Vamplew said. "I had to get lucky to win. I won a few all-ins, but I’m pretty proud of the way I played. I’m pleased with myself for sure."
Juanda started the final table in a dead heat for the lead with online star Kyle Bowker.
But after Bowker dropped out third, Juanda entered heads-up with close to a 5:1 chip lead.
Vamplew fought back, however, turning the tide when he rivered a flush after getting it in against Juanda's turned Broadway straight to double up.
Vamplew is now the top-earning Scottish player of all time while Juanda leapfrogged WSOP Main Event winners Peter Eastgate, Joe Hachem and Scotty Nguyen to move up to fifth on poker's all time leading money winners list.
EPT Berlin finalist Artur Wasek finished fourth while NAPT Venetian champ Tom Marchese took eighth.
A total of 848 players entered the event creating a £4,112,800 prize pool and making EPT London the largest tournament in UK history.
The field included 165 players who won their seats on PokerStars.
Across the room at the Hilton Metropole, back-to-back LAPT winner Nacho Barbero took down the EPT London £20,000 High Roller event.
Barbero earned £556,000 for the win after getting past a 77-player field and a final table that included Jani Sointula (2nd) and Vanessa Selbst (4th).
Next up for the European Poker Tour is the €5,300 EPT Vienna main event in Austria Oct. 26-31.
Here's how the final eight finished up in the EPT London main event:
1 David Vamplew £900,000
2 John Juanda £545,000
3 Kyle Bowker £300,000
4 Artur Wasek £240,000
5 Kayvan Payman £190,000
6 Fernando Brito £145,000
7 Tom Marchese £100,000
8 Per Ummer £66,800