The 156-acre site at Shawfield straddles the border between Glasgow and South Lanarkshire Council areas.
Over the next 25 years, large swathes of land contaminated by heavy industry will be cleaned up.
The aim is to create a National Business District, which could feature a 150-bed hotel, conference facilities, restaurants, a casino and shopping.
Glasgow is responsible for about a fifth of the land with the remainder in South Lanarkshire.
Both councils have now approved the masterplan which is aimed at building on the completion of the M74 and the East End Regeneration route.
It sets out to deliver a long-term, sustainable and low carbon development over a period of between 20 to 25 years, with construction taking place over an 18-year period.
Richard Brown, the city council's executive director of de velopment and regeneration, said: "The Shawfield area is dominated by areas of vacant and derelict brownfield land, as well as examples of long-standing business and industrial premises and commercial, retail and leisure uses."
The area to be redeveloped is bounded to the south by the M74, to the north by the River Clyde, to the north-west by Shawfield Drive and to the east by the Argyle rail line.
Mr Brown said: "The site is significantly constrained by existing levels of contaminated land and the remediation of this contamination forms a major component of the development proposals."
The masterplan is at an early stage and does not yet contain details of exactly what will make up the new National Business District.
But it is likely to be divided into areas for leisure, industry, business and corporate headquarters. No use has yet been identified for the fifth and final area.
It is also planned to upgrade Shawfield Cross and create a new civic square and to create a new river promenade on the south bank of the Clyde suitable for walking or cycling.
The scheme is the brainchild of Clyde Gateway regeneration agency, which covers a large part of the East End of Glasgow, including Bridgeton, Dalmarnock and Parkhead, Rutherglen and Shawfield.
It will oversee more than £1.5billion of private and public sector investment in the area, creating around 20,000 jobs.
Clyde Gateway chief executive Ian Manson said: "The National Business District, which will flank both sides of the River Clyde, is the key to unlocking enough sites to ensure we meet the 20 years jobs target within Clyde Gateway.
"Yesterday's decision gives us the green light to get two vital bits of work under way almost immediately.
"The first of these will be a £15m investment into the Shawfield area which will tackle the severe infrastructure problems that have been a blight on the area for almost half-a-century.
"The other is the awarding of a contract for the construction of a £24m office development on the Dalmarnock side of the river.
"Our work and activities will create the best possible conditions for other developers and investors to come here and be part of an ever-growing success story.
"The precise details of the layout of the National Business District will be determined by the commercial and property markets, but there is capacity for some 350,000sq m of space capable of supporting 15,000 jobs in the office, industrial, storage and distribution sectors."