After battling through smoke to check the pub for any occupants, the firefighters found a part of the first-floor was alight.
There were no reports of any injuries.
The mock-Tudor pub has been derelict since 2006 but there were recent plans to turn it back into a bustling 90-bedroom hotel.
In 2017, it was up for auction with a guide price of £2,000,000.
The Grade II listed pub, built-in 1932, is on Historic England’s Heritage At Risk register.
Local residents have growing concerns after the pub has faced repeated vandalism and a different fire in 2016 damaged the roof.
Station Commander James Ryan, who was at the scene, said: “Crews were faced with a significant amount of smoke issuing from the building when they arrived, which had prompted a high volume of calls to our Control Officers.
“Firefighters carried out a systematic search of the building and fortunately, there were no people involved.
“There are significant local road closures in place including Station Road in both directions from the junction with Manor Park Crescent to the junction with Methuen Road.
“We would advise motorists to avoid the area where possible as there is heavy traffic and we will be on scene damping down for some time.”
In 2003, Historic England gave the Railway Hotel a grading. It noted that, “It is among the best examples of a picturesque roadhouse in the country”.
Mark Amies, a local historian who has set up several petitions to save the site, tweeted to say too heartbroken to visit the site.
He wrote: “I’m angry because all those who were supposed to be protecting this Grade 2 listed building have failed it.
“The Railway Hotel has sat unused and unloved for over 11 years. It had several owners, none of whom did anything with it.”
The London Fire Brigade said the cause of the fire is under investigation.