More than 500 US Air Force (USAF) personnel and their families will move from a closing air base by 2023.
The USAF and Ministry of Defence (MoD) has announced two squadrons at RAF Mildenhall will be relocated to RAF Fairford in Gloucestershire.
The closure of the Suffolk base was announced in 2015 but the plan has been delayed.
It is expected the move will bring "substantial" financial benefits for the Cotswolds.
From RAF Fairford, the USAF personnel - part of the 95th Reconnaissance Squadron and the 488th Intelligence Squadron - will provide the support mission for the RC-135 surveillance aircraft. The base is already the only European base for American heavy bombers.
The move was announced by Defence minister Tobias Ellwood.
He said: "For more than a hundred years now our armed forces have fought in defence of our common values and interests. Our two countries have developed the deepest, broadest and most advanced defence relationship of any two nations.
"The agreement to relocate the United States Rivet Joint capability to RAF Fairford cements US presence at the base and will bring substantial benefits to Gloucestershire and local communities."
As part of the relocation - which will involve flight crew, maintenance, intelligence analysts and communications personnel - there will be some infrastructure work and the MoD has said it is expected to bring "financial benefits".
Cotswolds MP Sir Geoffrey Clifton-Brown said: "The presence of over 1,200 personnel and dependants to the area will bring substantial financial benefits to the local economy and our local community."
RAF Mildenhall is home to more than 3,000 personnel as well as another 1,000 dependents and USAF Europe estimates the base has a £230.73m economic impact on the local area.
The MoD believes the full US drawdown from Mildenhall will not be completed until 2024 at the earliest.
West Suffolk MP Matt Hancock said the "last thing we want is for the base to be mothballed".
The Conservative MP said: "As and when the drawdown happens we need to make sure we use the land in a sensible way that benefits the local area and crucially make sure all of the people who are affected are supported."
RAF Mildenhall is home to some 325 USAF officers, 2,797 enlisted personnel, 381 US civilians and 651 local nationals.
As well as the two squadrons leaving it has 100th Air Refueling Wing, 501st Combat Support Wing, 352nd Special Operations Wing and 727th Air Mobility Squadron.
Aircraft housed at the base include vertical takeoff aircraft CV-22 Osprey, air refuelling jets KC-135 and R-135.
RAF Mildenhall has been controlled by the USAF since 1950 and has been in operation since 1934.