Around 1,000 new jobs could be created after the owners of the Odyssey won planning permission for an extension to include hotels, shops and apartments.
Work is due to start immediately, with around 800 people set to work on construction of the scheme – described as the biggest redevelopment in Belfast in years.
Odyssey Trust's plans to build next to the existing Odyssey Arena and Pavilion come just weeks after Belfast Harbour won planning permission for an office development at City Quays.
With an application lodged by Titanic Quarter Ltd for yet another development, the entire Belfast Harbour area is set for a major growth spurt.
The scheme has space for nearly 800 apartments, two hotels, shops, cafes, bars and restaurants and "community and cultural use" space, according to planners Turley Associates, which acts for Odyssey Trust.
The planned shops and cafes will bring new amenities to the doorstep of residents and office workers at the Titanic Quarter.
Turley Associates said the apartments would include some shared equity and co-ownership units.
Brian Hughes, operations director of Odyssey Trust Company, said: "This is a major milestone towards the redevelopment of Queen's Quay at Odyssey.
"It has always been our ambition to create an exemplar mixed-use space that will enhance the success of Odyssey.
"The development will create a seamless connection between the city centre and the extensive Titanic Quarter, providing an extended leisure offer, new homes and much-needed quality jobs."
The plans were first submitted in 2009, according to Turley Associates' Sheila Murphy. "It is the largest redevelopment scheme the city has seen for many years and will complete and complement Odyssey."
She said approval was "timely" as it coincided with a review of the council's Belfast City Masterplan, and said the development reflected the aims of the plan.
"We consider that the Odyssey together with other major redevelopment proposals along the River Lagan will perform an essential role in growing the city and the status of these deliverable projects should be promoted as strategic within the masterplan."
Last month, Belfast Harbour won planning approval for its Grade A office development City Quays 1 near Belfast Harbour Office at Clarendon Dock.
And in September, Titanic Quarter Ltd lodged a planning application for new offices beside Belfast Metropolitan College's Titanic Quarter campus.
It's now 13 years since the Odyssey was unveiled as Belfast's Millennium Project and since then, the arena has played host to hundreds of pop stars and bands.
However, the pavilion has had a more chequered history after it was repossessed by then Anglo Irish Bank over the borrowings of developer Peter Curistan, who masterminded the original Odyssey concept. It was put on the market at £10m.
Mr Curistan then sued the bank, later the Irish Banking Resolution Corporation, alleging fraudulent misrepresentation and negligence over the steps it took to find a buyer for his lease on the pavilion.