There is some evidence of Roman activity in the parish. Roman pottery was found close to Verney Junction and near Sandhill House in fieldwalking surveys and suggests the site of a building somewhere nearby. The medieval hermitage of Finemere may have been where a building platform can still be seen near Claydon Woods.
Middle Claydon is mentioned in Domesday and was part of Bernwood Forest from before this time. Bernwood had been a hunting forest from the time of Edward the Confessor. It grew to its largest extent under Henry II. The whole area was not covered by woods; in the medieval period a forest was a place where deer roamed for hunting and so included open land, villages and fields. All those who lived in the forest were not allowed to hunt or even gather wood without a special licence from the king. Bernwood Forest was finally disafforested in the reign of James I in 1635, although it had been shrinking in size since the time of King John (1199-1216).
Middle Claydon manor passed through various hands in the medieval period, finally to the Wrights and Calverts who took the name and arms of a previous incumbent, the Verneys. A windmill is recorded at the manor house in the 14th century. Claydon House was originally a 16th century manor house, though the current house is an 18th century adaptation. Part of the house is still home to the Verneys and part is looked after and opened by the National Trust. The gardens were landscaped in the 18th century and have ornamental bridge, pavilions and lodges. There are records that the medieval village was levelled in the 18th century to make way for these gardens. All Saints church, dating back to the 14th century, still stands in the grounds of the manor house. The Verneys rebuilt the village almshouses along the nearby road in the late 17th century.
Earthworks seen from the air near Coppice Lowhill may be the remains of post-medieval buildings, or possible animal enclosures with associated buildings. There are also ponds, possibly for watering animals. 19th to 20th century brickworks are recorded north of Claydon House and are now just a series of ponds and marshy areas. This may also be the site of the 17th century brickworks that made many of the bricks used in Claydon House. One of the latest changes to the parish was the Aylesbury to Buckingham railway, opened in 1868 and run by various railway companies over the years. It was closed in 1936 as it was unprofitable and then reopened at the end of the Second World War for three years but then closed again. Verney Junction was an important crossing point for several railways, for instance the Bletchley-Banbury line (opened 1851), as well as a railway station, which was closed in 1968.