The road has been re-routed several times in the last 100 years – part of the route of the London section of the A40 was laid out in the 1920s and 1930s when Western Avenue was built – now most of it is grade-separated, dual carriageway (divided highway).

After crossing the southern end of Tottenham Court Road (the A400) at St Giles Circus, the A40 becomes Oxford Street.

The busiest stations are Tottenham Court Road, Oxford Circus, and Bond Street, which provide access to five tube lines.

The road forms the northern boundary of Soho; the main theatres and cinemas are located to the south near Leicester Square.

Nearby is Speakers' Corner, where people are generally allowed considerable freedom of speech, although the police occasionally intervene.

It was constructed between 1964 and 1970 to relieve congestion at Shepherd's Bush, with traffic from Western Avenue struggling to enter central London along too narrow roads.

Eastbound traffic from the Westway cannot exit here to reach the Edgware Road and must continue ahead to the Marylebone Flyover.

Leaving Marble Arch, the A40 continued along Bayswater Road and Holland Park Avenue (now the A402) running through Notting Hill Gate to Shepherd's Bush.

Still busy, the Uxbridge Road was redesignated the A4020, when Western Avenue was changed from being the A403, and the A40 route changed accordingly, From Shepherd's Bush, the A40 moved northbound along Wood Lane – near the BBC Television Centre  – to join Western Avenue adjacent to a roundabout with the M41, now the A3220, also referred to as the West Cross Route.

From this point the A40 swings in a north-westerly direction towards North Acton, crosses the Great Western Main Line, and the final traffic light controlled junction known as 'Gypsy Corner' (A4000), to arrive at the Hanger Lane Gyratory System to connect with the A406 and A4005.

The West Cross Route in The Royal Borough of Kensington and Chelsea and the Hammersmith and Fulham borough, was formerly the M41 motorway, part of the innermost circuit of the London Ringways network – a complex and comprehensive plan for a network of high-speed roads circling central London.

A grade-separated junction was built approximately halfway along this section of the A3220 in 2008 to connect to the Westfield London shopping development.

This shopping precinct in White City (London Borough of Hammersmith and Fulham) is on a site bounded by the West Cross Route, Westway and Wood Lane (A219), and opened on 30 October 2008.