Stratford station opened on 20 June 1839 when the Eastern Counties Railway ran its first trains. The original building sat on Angel Lane, accessed via an over-bridge to the east of the tracks. Almost immediately, more lines arrived: the Northern and Eastern Railway joined the ECR at Stratford on 15 September 1840, and a locomotive works was established adjacent to the line. The ECR had made an unusual choice for its track gauge—not the standard gauge that would eventually win out across Britain, but something narrower, on the recommendation of engineer John Braithwaite, to reduce wear on locomotive parts. By the early 1840s it was obvious this was a mistake. The conversion to standard gauge took place between September and October 1844.

The station grew constantly, absorbing new operators and new lines as London's rail network spread outward. By 1862 it had become a Great Eastern Railway station. By 1923 it was part of the London and North Eastern Railway. London Underground's Central line reached Stratford on 4 December 1946. The Docklands Light Railway arrived on 31 August 1987, reusing redundant route corridors through Bow and Poplar to reach the new developments on the Isle of Dogs. Each expansion brought more passengers and more complexity. An accident on 8 April 1953—a rear-end collision in a tunnel east of the station—killed 12 people and injured 46. It remained London Underground's worst fatality accident until the Moorgate crash of 1975. The station kept growing.

The biggest single transformation came in preparation for the 2012 Olympics. The station's capacity was tripled at a cost of around £200 million, with £125 million from the Olympic Delivery Authority and the remainder from Westfield. Construction ran from 2005 to 2011. Fourteen new lifts provided step-free access to every platform. A new mezzanine entrance linked the southern side of the station to a pedestrian bridge over the railway funded by Westfield. New high-level platforms were built for the Overground. The work expanded a station that had been designed around nineteenth-century rail volumes to handle what became 120,000 people at peak Olympic periods—then, after the Games, continued growing. By 2019 passenger movements reached 128 million annually. The station is now Britain's seventh busiest railway station and the busiest outside London fare zone 1.

Stratford station today operates across multiple levels, running roughly east-west at the high level and north-south at the low. It serves the Central and Jubilee lines underground, the Elizabeth line and Greater Anglia services on the main line, the London Overground's Mildmay line, the Docklands Light Railway, and c2c services to Essex. At one point in its electrification history, the station simultaneously used four different electrical systems—a record for any station in London. The Jubilee line platforms, built in the late 1990s, sit at ground level with a footbridge carrying passengers down from the main concourse. Stratford International, 370 metres to the north, handles domestic high-speed services to Kent, though its name is something of an overstatement: no international trains call there and the Eurostar has no plans to serve it.