Bitterne is thought to be named after the bend in the River Itchen – the Old English words byht and ærn together mean "house near a bend".
In 1665, Bitterne’s population was estimated to be 75 inhabitants, across just 15 houses.
A new estate was built in 1760, known then as Bitterne Grove, and a number of workers' cottages were erected in the Mousehole area to support the estate and farming activities at Bitterne Manor.
In the 1790s, frequent royal visits to Southampton encouraged a spate of land-buying in the area, and further estates were added, including Ridgeway, Sydney Farm and Midanbury Lodge. Townhill Park House was built, and Chessel House was built in 1796 by David Lance. Aware that access to his land was poor, Lance encouraged the building of a bridge over the River Itchen linking Bitterne Manor to Northam, and another bridge over the River Hamble at Bursledon. The bridges were to be linked by a road which would join another new road to Botley. Work on the new roads and bridges – which would become an important communications route - was completed in 1801.
By the 20th century, Bitterne Village was swallowed up by fast-expanding Southampton. In the 1950s, the area underwent extensive renovation, with Victorian cottage housing areas demolished and flats and estates erected on the old farmland.
During the 1980s, work was carried out to bypass the bottleneck of the main high street by looping the A3024 from the top of Lances Hill eastwards through to a new junction with the Hedge End road. The old post office and United Reformed Church were demolished, and the completion of this work enabled the pedestrianisation of the old high street.