The scheme is designed to protect against floods like those that wreaked havoc across England this summer. Up to 530 homes and businesses are expected to benefit from the work, which will be completed in two years.
West Ham was affected by storms in July 2007, August 2002 and September 2004, when unseasonal rainfall overwhelmed the system.
"Sewer flooding is an unpleasant and distressing experience. It's vital that we make these improvements to reduce the risk of it recurring," said Thames Water project manager Robert Griffiths.
"This project in West Ham is going to be the biggest project of its type that we're undertaking in London and it should protect hundreds of our customers. I want to reassure residents, traders and motorists that we'll do all we can to minimise any disruption."
Engineers will be enlarging the existing sewers in 46 roads within the E7 postcode, with much of work being carried out through underground tunnelling to minimise surface disruption to residents.
A new 3m diameter, 3km long tunnelled sewer will carry away excess rainwater runoff and sewage during storms, preventing flooding back into streets.