The company has been given the green light to press ahead with plans to axe 22 stores, including the Mander Centre branch which only opened two years ago.
A total of 1,200 jobs are set to go as part of the restructure.
Emma Reynolds, MP for Wolverhampton North East, insisted it was crucial the empty unit left behind was filled quickly.
It is understood House of Fraser is considering moving in from Beatties.
Ms Reynolds said: "It is hugely disappointing that Debenhams is to close its flagship Mander Centre store, after spending a lot of money refurbishing and opening it just two years ago.
"The closure will be particularly disappointing for the staff, who must be supported by Debenhams to find training or alternative employment.
“Debenhams was the anchor tenant and a core part of the Mander Centre, and its closure will leave a huge hole to fill in the city centre.
"The priority now must be to find a new use for the store with a company actually committed to Wolverhampton’s high street retail.
"I regularly shop in the city centre with my family and know the city centre cannot afford to have more empty units."