It has been a port since the 12th century or earlier, and a shipyard since Elizabethan times. It was the site from which the Mayflower set off on part of its journey to carry the Pilgrim Fathers to Virginia in 1620. The ship's captain, Christopher Jones, lived in Rotherhithe and was buried there in 1622.

The name 'Rotherhithe' derives from an Anglo-Saxon word meaning "landing-place for cattle". The first recorded use of the name was in about 1105. In the past Rotherhithe was also known as Redriff until the early 19th century. Redriff was the fictional birthplace of Jonathan Swift's character Lemuel Gulliver.

Edward III had a palace at Rotherhithe and in 1412 Henry IV stayed in the area 'whilst he was cured of leprosy'. It was hoped the sea air would help his complaint. He arrived by river, sailing down the Thames from the Palace of Westminster to Rotherhithe.

The village of Rotherhithe has had a close relationship with the sea. Throughout history it was a favourite home for many seafarers, such as Captain Christopher Jones of The Mayflower, and had a fine tradition of shipbuilding. Two local Master Mariners, Peter Hills and Robert Booth, founded a school to help the children of destitute sailors in 1613.

Rotherhithe became home to shipbuilders. Some of the first steamships were built in Rotherhithe and the first iron ship, the Aaron Manby, was constructed in the local shipyards. Rotherhithe was also home to many associated industries, for example iron works and gun powder manufacturers. The names of the local docks reflect the days gone by, Greenland Dock is a reminder that whalers used to be based there. The dock was called Howland Great Wet Dock from its foundation in 1693 until 1763 and was the largest commercial dock in the western world at the time, able to handle 120 merchant ships. It was the major whaling base in London until the trade died in the 1840s, after which it was used for the importation of timber.

Improving transport saw the population of Rotherhithe rise. In 1801 it housed 10,296, a century later it was home to 38,424. The housing tended to be mixed - the rich enjoyed comfortable housing whilst the poor endured the very worst.

Because much of the former Surrey Docks had strong trade links to Scandinavia and the Baltic region the area is still home to a striving Scandinavian community. Originally established as seafarers' missions, Rotherhithe is home to a Norwegian, a Finnish and a Swedish church.

The docks were closed and largely filled in during the 1980s, and have now been replaced by modern housing and commercial facilities, but Rotherhithe retains much of its character and its maritime heritage. The largest surviving dock on the south bank, Greenland Dock, is the focal point for the southern part of the district, while there are many preserved wharves along the riverside at the north end of Rotherhithe. St Mary's Church is at the centre of the old Rotherhithe village, which contains various historic buildings including the Brunel Engine House at the south end of the Thames Tunnel.

Rotherhithe station was originally opened on 7 December 1869 when the first section of the East London Railway was opened, running through the Thames Tunnel. On 1 October 1884, the Metropolitan and Metropolitan District Railways began running services along the East London Railway, which called at Rotherhithe. It was served by electric passenger trains from 31 March 1913, when the line was electrified. Steam-hauled goods trains from Liverpool Street station continued to pass through until April 1966. The station was closed between 1995 and 1998 due to repair work on the Thames Tunnel and from 22 December 2007 to 27 April 2010 for the extension of the East London Line. The station re-opened on 23 May 2010 on the London Overground.