Hogesdon is first recorded in the Domesday Book, meaning an Anglo-Saxon farm belonging to 'Hoch', or 'Hocq'. Little is recorded of the origins of the settlement, though there was Roman activity around Ermine Street, which ran to the east of the area from the 1st century. In medieval times, Hoxton formed a rural part of Shoreditch parish.

In 1415, the Lord Mayor of London caused the wall of the City to be broken towards Moorfields, and built the postern called Moorgate, for the ease of the citizens to walk that way upon causeways towards Islington and Hoxton – at that time, still marshy areas. The residents responded by harassing walkers to protect their fields. A century later, the hedges and ditches were destroyed, by order of the City, to enable City dwellers to partake in leisure at Hoxton.

By Tudor times many moated manor houses existed to provide ambassadors and courtiers country air nearby the City. The open fields to the north and west were frequently used for archery practice, and on 22 September 1598 the playwright Ben Jonson fought a fatal duel in Hoxton Fields, killing actor Gabriel Spencer. Jonson was able to prove his literacy, thereby claiming benefit of clergy to escape a hanging.

On 26 October 1605 Hoxton achieved notoriety, when a letter arrived at the home of local resident William Parker, Lord Monteagle warning him not to attend the Parliament summoned by James I to convene on 5 November, because "yet I say they shall receive a terrible blow, the Parliament, and yet they shall not see who hurts them". The letter may have been sent by his brother-in-law Francis Tresham, or he may have written it himself, to curry favour. The letter was read aloud at supper, before prominent Catholics, and then he delivered it personally to Robert Cecil at Whitehall. While the conspirators were alerted, by the public reading, to the existence of the letter they persevered with their plot as their gunpowder remained undiscovered. William Parker accompanied Thomas Howard, the Lord Chamberlain, at his visit to the undercroft of Parliament, where Guy Fawkes was found in the early hours of 5 November. Most of the conspirators fled on the discovery of the Gunpowder Plot, but Francis Tresham was arrested a few days later at his house in Hoxton.

By the end of the 17th century the nobility's estates began to be broken up. Many of these large houses became to be used as schools, hospitals or mad houses, with almshouses being built on the land between by benefactors, most of whom were City liverymen. Aske's Almshouses were built on Pitfield Street in 1689 from Robert Aske's endowment for 20 poor haberdashers and a school for 20 children of freemen. Hoxton House, was established as a private asylum in 1695. It was owned by the Miles family, and expanded rapidly into the surrounding streets being described by Coleridge as the Hoxton madhouse. Here fee-paying 'gentle and middle class' people took their exercise in the extensive grounds between Pitfield Street and Kingsland Road;[14] including the poet Charles Lamb. Over 500 pauper lunatics resided in closed wards, and it remained the Naval Lunatic Asylum until 1818. The asylum closed in 1911; and the only remains are by Hackney Community College, where a part of the house was incorporated into the school that replaced it in 1921. At this time Hoxton Square and Charles Square were laid out, forming a fashionable area. Non-conformist sects were attracted to the area, away from the restrictions of the City's regulations.

In the Victorian era the railways made travelling to distant suburbs easier, and this combined with infill building and industrialisation to drive away the wealthier classes, leaving Hoxton a concentration of the poor with many slums. The area became a centre for the furniture trade.

Manufacturing developments in the years after the Second World War meant that many of the small industries that characterised Hoxton moved out. By the early 1980s, these industrial lofts and buildings came to be occupied by young artists as inexpensive live/work spaces, while exhibitions, raves and clubs occupied former office and retail space at the beginning of the 1990s. During this time Joshua Compston established his Factual Nonsense gallery on Charlotte Road in Shoreditch and organised art fetes in Hoxton Square. Their presence gradually drew other creative industries into the area, especially magazines, design firms, and dot-coms.

By the end of the 20th century, the southern half of Hoxton had become a vibrant arts and entertainment district boasting a large number of bars, nightclubs, restaurants, and art galleries.

The northern half of the district is more residential and consists largely of council housing estates and new-build private residences.

Hoxton railway station is in the Hoxton district of the London Borough of Hackney. The station is located on the Kingsland Viaduct and is served by London Overground trains on the extended East London Line, under the control of the London Rail division of Transport for London. The station is situated at the back of the Geffrye Museum and is on Geffrye Street near to Dunloe Street and Cremer Street.

The station was officially opened to the public on 27 April 2010, initially with week-day services running between Dalston Junction and New Cross or New Cross Gate. On 23 May 2010 services were extended from New Cross Gate to West Croydon or Crystal Palace.