The David Garrick pub in the Theatre District will cease trading on Sunday.
Staff from the Wetherspoon operated pub will relocate to other branches in the area.
“Wetherspoons, like many other companies has to look at its estates and make commercial decisions,” said Wetherspoons spokesman Eddie Gershon.
“It makes sense to the company, although we can understand that regular visitors will be disappointed.”
Wetherspoons owns 950 branches nationwide, and will still operate three in Milton Keynes.
“Owners of the Theatre District are disappointed to hear of the imminent closure of The David Garrick,” said Theatre District marketing manager Sara Mills, on behalf of UGS (MK) Ltd.
“Obviously JD Wetherspoon have their own financial and strategic reason for this decision.
“The Theatre District is continuing with plans to build the 130 room Premier Inn hotel and a contractor has been selected with the view to start work on site in the summer 2016.
“They are also committed to improving the area withlighting already enhanced, planting possibilities being investigated and a major cleaning project in hand.
“The Theatre District is currently not on the market,” she added.