The fast food operator has taken on a former retail unit on Magdalen Street, and received outline planning permission for the change of use last year.
A site in Reading has already been secured, and will mark the group's first opening in the UK since it pulled out of the market just over 20 years ago.
Speculation that Wendy's was looking to return to UK shores had been rising since a one-day pop-up in London back in 2017, which many regarded as an opportunity for the chain to test the waters for a re-entry into the UK.
The chain previously operated around 10 restaurants across the UK, including high-profile London sites on Shaftesbury Avenue - which is now occupied by McDonald’s - and Oxford Circus.
However, it made the decision to leave in 2000, surrendering its leases in order to concentrate on its domestic North American market
A spokesperson for Wendy's said: "I can confirm that we will be opening a Wendy’s restaurant in Oxford.
"Our first location is in Reading and we are exploring additional opportunities in the London area. The brand is excited to enter the UK with company owned and operated restaurants this year, and we are looking for franchisees to grow with us across the United Kingdom."
Founded in Ohio in 1969, Wendy’s has more than 6,700 outlets in 30 countries around the world.