Mosley was previously general manager at Norton Park in Winchester, where he oversaw a £14m investment in the hotel.
He replaces Michael Knox Johnston at The Grand.
It is Mosley's third stint at De Vere, which owns The Grand. He began his career as a porter at Royal Bath in Bournemouth and later worked as director of operations at The Belfry.
"I'm looking forward to working closely with Visit Brighton and other industry partners in Brighton to attract more conference business to The Grand," said Mosley. "It's fantastic to be given the responsibility of heading up such an iconic hotel as The Grand."