The huge project will see the opening of the Silvertown Tunnel in 2025, with it hoped that it could slash travel time across the river Thames by 20 minutes.
Drivers hoping to head across the Thames into South London will be forced to divert around three miles in order to cross the Rotherhithe Tunnel.
The A13, which serves the tunnel and runs from Canning Town to Whitechapel, is also expected to see significant disruption.
The only other crossing sits 20 miles to the east in Dartford, with East London having a shocking lack of bridges and crossing points compared to West London.
The Woolwich Ferry will continue to operate as normal while the 108 bus will provide a “split service” throughout the weekend.
TfL has also urged HGVs and large vehicles to avoid central London and consider weight and height restrictions when using alternative routes.