The blaze at a commercial building on the North Circular in Neasden halted traffic on the ring road in both directions between Neasden Lane North and Staples Corner, where the key route meets the M1, in the early hours of Wednesday.
Transport for London (TfL) said the M1 had also been closed southbound at the interchange and urged motorists to use alternative routes.
The London Fire Brigade (LFB) said 10 fire engines and 70 firefighters were tackling the fire on the first floor of a nearby warehouse, while the Metropolitan police had sent officers to the scene.
Transport for London Traffic News tweeted at 5.34am: “Reminder for the early birds – the A406 North Circular Road is CLOSED BOTH WAYS between Neasden and Staples Corner Flyover due to a large building fire between the two.
North Circular traffic updates as A406 is closed at Brent Cross
Scotland Yard tweeted: Were assisting @LondonFire at a warehouse fire on the A406 in #Neasden, Road closures likely to severely affect North Circ Rd, Staples Corner and other key routes into morning rush hour. Drivers should avoid the area.
Dramatic blaze tears through warehouse and forces closure of Londons North Circular
LFB tweeted: Ten fire engines & around 70 firefighters are tackling a blaze in a commercial building on North Circular Road in #Neasden. Half of the first floor is alight.
Londons North Circular was closed in both directions after a fire broke out at a commercial building in Neasden, however it has since re-opened.
The blaze halted traffic on the ring road in both directions between Neasden Lane North and Staples Corner, where the key route meets the M1, in the early hours.