Plumes of smoke billowed into the air as firefighters battled a blaze near Oxford Street.
Video posted on social media showed thick, grey smoke rising into the air just off the busy street as shoppers covered their faces.
Firefighters rushed to the scene of the fire in Vere Street, by Debenhams, just before 3.30pm on Sunday.
A restaurant and five floors of office space were affected, a spokeswoman for the London Fire Brigade said.
Some 50 people were forced to flee the building.
Charlotte Hunter, from Chislehurst near Bromley, was in Debenhams when the fire broke out. She said the department store evacuated all its shoppers.
She told the Standard: "The smoke was very thick and blowing down Oxford Street.
"People were calm and emergency services attended quickly.
"It looked like the fire was in the roof. They [the firefighters] were spraying the roof."
One person tweeted: "Fire on Oxford Street. Area full of smoke. Try and avoid if possible."
Others said there was "strange smelling gas" and "smoke everywhere".
The Brigade was called at 3.26pm and sent five fire engines and 30 firefighters to the scene.
A spokeswoman said: "Firefighters are tackling a fire in a restaurant on Vere Street, Marylebone, central London. The restaurant’s ventilation system is alight."
