Police are appealing for witnesses after the White Swan pub on Mansbridge Road, Swaythling, was burgled overnight on Sunday, July 31 and Monday, August 1.
Burglers struck sometime between midnight and 7.30am, entering through a gate to the left of the building and then forcing entry through a window.
Once inside they located the safe which was emptied of an undisclosed amount of money.
Investigating officers are asking for anyone who may have witnessed the incident or have any information to contact PC Mark Kingston at Bitterne police station on 101 or call the Crimestoppers charity line on 0800 555 111.