It is hoped that by improving the riverside habitat and water quality, the three-year, pounds 170,000 scheme will encourage the mammals to return to the river and its tributaries in Surrey, Berkshire, Buckinghamshire and Oxfordshire.
Wild otters were last resident in the Thames region in the 1970s, before intensive agricultural pesticides and damage to their habitat led to their decline.
Signs of otters have been found in the area in recent years, suggesting that a small number of transient otters are seeking territories in the Thames region.
Local people will be involved in recovery efforts and in raising awareness of the plight of the otter.
Sir David said: "The otter is one of our most enchanting animals. Everyone will benefit if we succeed in this. It is a chance for us to put right some of the damage done to our wildlife."
Between the late 1950s and the 1970s otters were brought to the verge of extinction by a mixture of hunting, pollution and encroachment on their environment by expanding towns.
Contamination by agricultural pesticides and fertilisers was pinpointed as one of the main causes of the decline, causing fish stocks in rivers to dwindle and starving otters from their natural habitat.
Conservation efforts over the past 20 years have seen the British otter's fortunes restored, with numbers reaching 3,000. The Government has pledged to reintroduce the otter to all its pre-1960 habitats by 2010.
The scheme is part of the National Otter Biodiversity Action Plan, which was launched last summer.