Historically a part of Lancashire, there are records of Didsbury existing as a small hamlet as early as the 13th century. Its early history was dominated by being part of the Manor of Withington, a feudal estate that covered a large part of what is now the south of Manchester. Didsbury was described during the 18th century as a township separate from outside influence. In 1745 Charles Edward Stuart crossed the Mersey at Didsbury in the Jacobite march south from Manchester to Derby, and again in the subsequent retreat.
The Royal Society for the Protection of Birds was formed in Didsbury in 1889.
Didsbury derives its name from the Anglo-Saxon Dyddi's burg, probably referring to a man known as Dyddi whose stronghold or township it was on a low cliff overlooking a place where the River Mersey could be forded. In the 13th century Didsbury was variously referred to as Dydesbyre, Dydesbiri, Didsbury or Dodesbury.
A charter granted in about 1260 shows that a corn-grinding mill was operating in Didsbury, along the River Mersey, but the earliest reference to Didsbury is in a document dating from 1235, recording a grant of land for the building of a chapel. The church was named St James Church in 1855. It underwent major refurbishment in 1620 and again in the 19th century, although most of the stonework visible today dates from the 17th century. A parsonage was built next to one of the two public houses that flanked the nearby village green, Ye Olde Cock Inn, so-called because of the cockfighting that used to take place there. The parsonage soon gained a reputation for being haunted; servants refused to sleep on the premises, and it was abandoned in 1850. Local alderman Fletcher Moss bought the house in 1865, and lived in it for more than 40 years. In 1902, he installed a gateway complete with wrought iron gates which he purchased from the soon to be demolished Spread Eagle Hotel in central Manchester which he once owned, at the entrance to the parsonage's garden, which, because of the building's reputation, became known locally as "the gates to Hell". The parsonage became a museum, now closed, but the gardens are still open to the public. The area around St James' Church has the highest concentration of listed buildings in Manchester, outside the city centre.