Ten fire engines and a height vehicle went to the scene at the Popinjay Hotel in Rosebank, South Lanarkshire, when the alarm was raised on Thursday morning.
There were no reports of any injuries.
In a post on social media, hotel staff said: "Fire incident at Popinjay Hotel this morning, we are able to let everyone know full evacuation of all staff and guests completed quickly without injury to anyone."
They said the property is in the hands of the fire service for investigation.
The Scottish Fire and Rescue Service said they were called to the scene at 7.18am.
A spokesman said: "Operations Control mobilised 10 fire appliances, one height vehicle and specialist resources to a fire affecting a commercial property.
"There are no reported casualties at this time and crews are still in attendance."
Police said part of the A72 was closed as emergency services dealt with the incident.