The agreement was announced after Mrs Clinton, the US secretary of state, met the Indian prime minister, Manmohan Singh, in the Indian capital.
S.M. Krishna, India's external affairs minister, said India had agreed to buy US defence equipment under an arrangement which will allow Washington to monitor its "end-use" to prevent weapons technology being sold on to rogue regimes.
The agreement puts the United States ahead of its rivals as India prepares to spend billions on modernising its armed forces, including the purchase of 126 fighter aircraft.
Lockheed Martin and Boeing are expected to benefit from the defence deal while General Electric and Westinghouse are expected to win substantial contracts to build reactors for two new nuclear power plants.
India is desperate to increase its power generating capacity to fuel its growing economy.
Its growing strategic partnership with the United States is a legacy of the former US president George W. Bush, and has been strengthened under President Obama.
It reflects Washington's need for a democratic partner in Asia to support its counter-terrorism efforts and as a check on China's expanding influence in the region.
As a mark of India's growing status in Washington, Mr Singh is due to pay a state visit to Washington.
Mrs Clinton was warmly received in New Delhi after she began her trip with a stay at Mumbai's Taj Palace Hotel, the scene of last November's terrorist attack. She has also won Indian hearts by pointedly not visiting its neighbouring rival, Pakistan.
She pledged to work with the Indian government to help reduce greenhouse gas emissions - Indian emissions are predicted to rise by 50 per cent by 2030 - and to modernise its agriculture.
But the deal focuses on defence and civil nuclear energy agreements which could be worth more than $40 billion to American companies.