The Flintshire-based Defence Electronics and Components Agency at Sealand will work with BAE Systems and Northrop Grumman on the project.
It will repair F-35 fighter plane components, including electronics and ejection seats.
Defence Secretary Michael Fallon said it was an endorsement of UK skills.
He said: "This establishes Britain as a hub for all European F-35s and is hugely positive news for our high-tech and innovative defence industry.
"It is an endorsement of the skills and capabilities the UK offers; will help create hundreds of high-end jobs, safeguard thousands more and be a substantial boost to UK exports.
"Building on the strong foundations of Britain's pre-eminent and enduring defence partnership with the US, this decision supports British jobs and helps keep Britain safer and more secure."
Welsh Secretary Alun Cairns said: "Today's announcement makes Wales an essential component repair hub for supporting the F-35 aircraft and confirms our status as a leader in aviation technology.
"I'm delighted that the expertise that exists in Wales, along with a skilled workforce, has been recognised by the award of this major contract. It will lead to the investment of millions of pounds into the economy of north Wales."
He said there were already about 400 jobs at the Sealand site, with thousands more in the supply chain, which would be "sustained and grown" over the coming years as a result of the announcement.
The repair service is expected to begin from early 2018.
The Ministry of Defence, which owns DECA, said the new work had the potential to unlock more than Â£2bn of future F-35 support income over the lifetime of the programme.
A north Wales defence agency has won a multi-million pound contract to help repair and maintain fighter aircraft from across Europe.