The Caltongate plans were passed by eight votes to six at a meeting of Edinburgh Council's development management sub-committee.
An international consortium headed by Artisan Real Estate Investors is behind the plans for leisure, retail and office space covering an area of around 220,000 sq ft linking New Street and East Market Street with Waverley Station and the Royal Mile.
The development will feature a £6.5 million civic square as well as office space, 400 hotel bedrooms and commercial units.
Residents and heritage groups opposed the plans and more than 5,000 people signed an online petition claiming they represented a "grave threat" to the Old Town's status as a Unesco World Heritage site.
Speaking after the scheme was approved, Councillor Ian Perry, convener of the planning committee, said the development would "breathe new life" into a derelict area previously the site of a bus garage and gas works.
He said: "First of all, I would like to thank those that have taken the time and effort to contribute to the debate about this site over the last 10 years.
"Following an 18-month consultation period on the current plans, it is great news that we finally have a decision on a development which I believe will breathe new life into a long-standing vacant site in the heart of the city.
"The plans we considered today will preserve the listed Canongate Venture building, the historic Sailor's Ark frontage on the Royal Mile, and give an exciting new life to the arches on East Market Street.
"There will be substantial investment across the site in the public realm and the creation of a new public square will make the area more attractive and pedestrian-friendly. A new viewing area will be built for people to enjoy the views to Calton Hill from Johnston Terrace.
"As the development has a mix of uses it will attract many more people to the area and with new housing on adjacent sites, including 40 affordable homes that are already being built, it will bring a real boost to the Old Town community.
"The economic benefit of this new development is huge and is estimated to bring in £43 million to the local economy each year, as well as creating almost 2,000 jobs."
Artisan previously obtained planning permission for 145 residential units and 40 affordable homes.