The incident happened at around 7am on Thursday morning, Lucerne cantonal police said in a statement.
The two men, one of which was armed, tied up an employee of the hotel and demanded money.
According to police the men were aged between 25 and 30, tall, wearing dark jackets and camouflage trousers and speaking in high German.
They are thought to have fled with an unknown sum of money in a red Seat Ibiza.
News agency ATS says the robbery is the second such incident in the past two weeks, after a hotel in Horn, in the canton of Thurgau, was robbed by two masked men who injured an employee.
Anyone with information on Thursday's robbery should contact Lucerne police on 041 248 81 17.