Before the 18th century, the land along which Euston Road runs was fields and farmland. Camden Town was a village retreat for Londoners working in the city. Euston Road was originally part of New Road, promoted by Charles FitzRoy, 2nd Duke of Grafton and enabled by an Act of Parliament passed in 1756. Construction began in May that year, and it was open to traffic by September.

The road provided a new drovers' road for moving sheep and cattle to Smithfield Market avoiding Oxford Street and Holborn, and ended at St John's Street, Islington. It provided a quicker route for army units to reach the Essex coast when there was a threat of invasion, without passing through the cities of London and Westminster, and was a barrier between the increasing urban sprawl that threatened to reach places such as Camden Town. A clause in the 1756 Act stipulated that no buildings should be constructed within 50 feet of the road, with the result that most of the houses along it lay behind substantial gardens. During the 19th century the law was increasingly ignored.

Euston Station opened on the north side of New Road in July 1837. It was planned by Robert Stephenson on the site of gardens called Euston Grove, and was the first mainline station to open in London. The Dukes of Grafton had become the main property owners in the area, and in 1857 the central section of the road, between Osnaburgh Street and Kings Cross, was renamed Euston Road after Euston Hall, their country house. The eastern section became Pentonville Road, the western Marylebone Road. The full length of Euston Road was dug up so that the Metropolitan Railway could be built beneath it using a cut-and-cover system and the road was then relaid to a much higher standard.

St Pancras station opened in 1867, with the Midland Grand Hotel in 1873.

The area around the junction with Tottenham Court Road suffered significant bomb damage during the Second World War. Patrick Abercrombie's contemporary Greater London Plan called for a new ring road around Central London called the 'A' Ring, but post-war budget constraints meant that a medley of existing routes were improved to form the ring road, including Euston Road. An underpass to avoid the junction with Tottenham Court Road was proposed in 1961, with construction taking place in 1964.


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