A revised masterplan for nearly 12,678 homes on a previously disused gasworks will create an entire new district formed of five neighbourhood zones.
The 80-hectare site previously stalled after a similar masterplan had been granted planning permission in 2004.
Developers Knight Dragon are already in the process of building a further 2,822 homes on the site, which will bring housing delivery on the Greenwich Peninsula to 15,720.
Plans also include 220 serviced apartments, 24,000 sq m of retail use, 60,000 sq m of business use, two new schools and two new hotels.
The development will also feature a 40,000 sq m film studio, a visitor attraction and increased green open space including an extension to the existing Central Park.
In August, Greenwich council gave outline planning permission for the site, which runs along the River Thames, and the Mayor has now also given the masterplan the go-ahead.
Developer Knight Dragon has 2,882 homes already under construction as part of existing planning permission.