Crowds gathered on the banks of the Thames to watch the 120-metre long model go up in flames.
The inferno in 1666 raged for four days, destroying most of the city, which then was largely of wood.
It paved the way for large-scale reconstruction including the building of today's St Paul's Cathedral.
More than 13,000 homes, businesses and structures, including the old St Paul's, were destroyed.
Following the fire, stone started being used in the capital as a building material and an organised fire service and insurance industry were established.
The burning of the replica of London took place during a festival held to commemorate the Great Fire.
London's Burning, which was held from 30 August to 4 September, featured a series of art installations, performances, talks and tours and was organised by the company Artichoke.
Helen Marriage, director of Artichoke, said: "I feel so relieved that it actually went off, because obviously when you do a live event you never know."
Tim Marlow, the artistic director of the Royal Academy of Arts, said it was a unique event.
He said: "I've seen a shed blown up in the name of art, I've seen fireworks, I've seen artists bury themselves, I've seen the trace of an artist shooting himself in the hand or nailing himself to a car, but actually I've never seen anyone collaborate with so many people in such an extraordinary and exciting way, to make a commemorative replica of a skyline 350 years ago and then set fire to it.
"I mean this is spectacle and then some."