Wates has been named lead contractor for the £200m Gresham Street development being brought forward by developers iMpeC and Buccleuch Property.
The transformational project sits as part of the wider Middlesbrough masterplan, with the first phase including more than 240 build-to-rent flats and residential accommodation for more than 450 students.
International hotel brand Fairfield by Marriott is also in talks to open a 200-bedroom hotel as part of the wide-scale regeneration project.
The project was approved by the Middlesbrough Development Corporation Planning Board and ranks as the biggest investment in the city for a generation.
The green light follows a recent land and asset transfer from Middlesbrough Council to the Development Corporation to pave the way for construction. Wates is understood to be aiming to start works this summer.
A new pedestrian footpath is also planned, connecting Diamond Road with Linthorpe Road and King Edward’s Square.
Tees Valley Mayor Ben Houchen said: “This is a landmark project for Middlesbrough.
“Our Development Corporation is playing a vital on by supporting major projects, cutting through planning red tape and getting on with the job of revitalising sites such as Gresham which have stood empty, unloved for far too long.”