The name ’Ratcliffe’ in Ratcliffe Highway means "red cliff", referring to the red sandstone cliffs which descended from the plateau on which the road was situated down to the Wapping Marshes to the south. The road forms an unofficial northern boundary of Wapping, which lies between the River Thames and The Highway.

A Roman bath house was excavated in 2004 by the junction of The Highway and Wapping Lane. The discovery of women’s jewellery along with soldiers’ possessions suggested that this location outside of the Roman walls allowed less restricted use of the baths than those in the City itself.

Ratcliff Highway once had different names for each of its sections. From west to east these ran: St George’s Street East, High Street (Shadwell), Cock Hill and Broad Street.

In the nineteenth century the road had a reputation for vice and crime and was the location of the Ratcliff Highway murders.

In the late 19th century Charles Jamrach, a dealer in wild animals, opened Jamrach’s Animal Emporium on The Highway. The store became the largest pet store in the world as seafarers in port sold any exotic animals they had brought with them to Jamrach, who in turn supplied zoos, menageries and private collectors.

At the north entrance to the nearby Tobacco Dock stands a bronze sculpture of a boy standing in front of a tiger, commemorating an incident where a Bengal tiger escaped from Jamrach’s shop into the street and picked up and carried off a small boy, who had approached and tried to pet the animal having never seen such a big cat before. The boy escaped unhurt after Jamrach gave chase and prised open the animal’s jaw with his bare hands. The tale was the inspiration for the 2011 novel Jamrach’s Menagerie by author Carol Birch.