The company is opening a restaurant at 3 The Moor next to H&M.
Hoardings have gone up around the premises. The company’s website confirms that it is opening ’very soon’.
It will have competition from Nando’s, Fat Hippo, El Paso, Dough & Co, Subway and Poundbakery.
It already has outlets at Meadowhall and Valley Centertainment in Attercliffe.
The Moor is Sheffield city centre’s busiest retail area but was rocked by the closure of Debenhams last year, which stands opposite the new Five Guys.
A large Sports Direct is set to open in the former TJ Hughes department store near Cumberland Street in July, with a St Luke’s charity shop opposite.
Founded in Arlington, Virginia, by the Murrell family, Five Guys employs 5,000 people, has 1,674 stores and had sales of $1.7bn last year.