The line is closed between Milton Keynes and Euston, affecting routes to the Midlands, north of England, Scotland and North Wales.
More than 50 firefighters tackled the blaze at a factory and offices in Chantry Place, Harrow.
Dozens of concerned residents phoned 999 after spotting the flames and huge plumes of smoke.
Network Rail said the blaze left a trackside retaining wall "in danger of collapse", which may take days to fix.
The fire has damaged a wall right next to the track. Engineers need to knock the wall down, but to do that they must bring in specialist kit and close the line so they can gain access to the site.
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