It is claimed that the five-year programme, expected to create around 500 jobs, and up to 50 new apprentices will transform the ageing network into a modern and sustainable drainage system fit for the needs of a 21st century city.
About 200 outfall pipes – safety valves used to control waste water during heavy rainfall – will be upgraded on the River Clyde and its tributaries.
The Scottish Environment Protection Agency (Sepa) said it was an "important step forward" in improving the natural environment of the River Clyde and alleviating sewer flooding in Glasgow. It forms part of a Wastewater Strategy, which Sepa said aims to enhance water quality in around 43 miles of the Clyde and its tributaries, and help "protect and improve bio-diversity" in the area.
Thirty years ago the Clyde was one of the world's most polluted waterways, with dead fish a common sign in the filthy, oxygen starved water. Salmon returned to the river in 1983 after a 120-year absence and the water has been teeming with wildlife.
Jennifer Leonard of Sepa said the strategy includes screening improvements to reduce the risk of sewage-related debris being discharged directly into the Clyde. That would stop rubbish such as sewage rags and nappies being found in the city's burns and parkland, she said.
Improvements will also be made in the south west of the city to remove excess surface water from "pinchpoints".
Nicola Sturgeon, Cabinet Secretary for Infrastructure, Investment and Cities, said: "This investment is essential to Glasgow's economic prosperity.
"It will improve the environment and ensure that new customers can connect to this essential public service."
Geoff Aitkenhead, Scottish Water's asset management director, said: "We are delighted to be starting this massive investment which will transform the network, help protect the natural environment and meet the needs of growth and development."
Gordon Matheson, leader of Glasgow City Council, said: "As a city built on the banks of the River Clyde, we are keenly aware of the importance of looking after our natural resources."