The Blackwall Tunnel will shut overnight southbound for two periods during August.
The closures – between August 16-20 and again from August 23-27 – are part of Transport for London’s £4billion road modernisation plan.
Work to resurface the road inside the tunnel as well as the A12 Blackwall Tunnel Northern Approach has already begun and will last until the end of the month.
Lane closures on the affected days will run from 11pm to 5am in a bid to avoid events at The O2.
During the closures, northbound traffic will be diverted through the southbound tunnel to keep traffic flowing from the A2 into London.
Southbound vehicles will have to follow routes using alternative river crossings including Tower Bridge and the Rotherhithe Tunnel.
In total traffic will be suspended southbound overnight for 10 days so resurfacing can be completed.
TfL chief operating officer for surface transport Garrett Emmerson said: “The Blackwall Tunnel carries around 100,000 vehicles a day under the river in east London, more than most sections of the M1.
“It is vital that we constantly maintain the tunnel to ensure that we can keep it open, safe and operational.”
Traffic and travel updates are available on TfL’s website .