Cannons, as it was once spelt, takes its name from the Augustinian canons or monks of the mediaeval Augustine priory of St Bartholomew in Smithfield, who owned the manor of Stanmore in 1086. At the dissolution of the monasteries it passed into the hands of Sir Hugh Losse in 1544, then to his son Robert, who sold the estate to Sir Thomas Lake, James I's Chancellor of the Exchequer, who replaced Losse's manor house by a mansion on a grander scale. Lake's great-granddaughter, Mary Lake, inherited Cannons and brought it in a dowry on her marriage to her cousin James Brydges in 1796 at Westminster Abbey.

Two years after his marriage to Mary Lake, James Brydges became MP for Hereford. He rose to the rank of Paymaster General to the Forces, a post which he left in 1713 having accumulated a fortune estimated at £600,000. Mary died in 1712, and in 1713 Brydges married his 43 year-old first cousin, Cassandra Willoughby. Around the same time he began the enlargement of Canons. In 1714 the couple and Brydges' two sons moved into the first completed part of the palatial new home.

In October 1714 Brydges inherited the earldom Caernarvon, which had recently been bestowed on his ailing father. In 1717 Bridges was created first Duke of Chandos and in the same year the composer George Frederick Handel became composer-in-residence at Canons. Handel wrote both The Chandos Anthems and Concerti Grossi at Canons, and his opera Acis and Galatea was first performed in the gardens. He remained at Canons until 1720.

In 1720, the year in which the building of the palace was completed, Chandos lost his fortune in the South Sea Bubble financial disaster. His wife Cassandra died in 1735, and a year later he married a 43 year-old widow (Lydia, Lady Davall) who brought with her a fortune estimated at around £40,000. Chandos eventually died in 1744, and his third wife died in 1750.

The palace at Canons was demolished in 1747 after the second Duke had sold off the great house and its effects in order to pay the accumulated family debts. The materials were auctioned for architectural salvage: the original colonnade now stands in front of the National Gallery in Trafalgar Square. The estate itself and the materials remaining on site were bought by William Hallett, a prosperous cabinet-maker turned gentleman, who built a country house on a relatively modest scale in 1760.

Hallett died in 1781 and upon the death of his grandson and heir in 1785, Canons was acquired by 'Captain' Dennis O'Kelly, a successful Irish adventurer and racehorse breeder, who made a fortune out of putting the great race-horse, Eclipse, to stud. Sir Thomas Plumer, Master of the Rolls, bought the estate at auction in 1805, and made a number of improvements to house and parklands. It was later acquired by Dr William Begg.

In 1887, following Dr Begg's death, it was auctioned for the last time and around 1896 Sir Arthur du Cros, a pneumatic tyre magnate acquired the house and surrounding grounds and commissioned Charles Mallows to design his gardens, which were considered to be amongst the greatest of the Edwardian era. The rest of the estate became the Canons Park Estate Company, selling the remaining land as building plots.

After the First World War, Du Cros put the house on the market and it was eventually bought by the North London Collegiate School in 1929 for the sum of £17,500.