Sir William Jones bought the estate in 1676. He wanted a country house to match his status, and turned to Dr Robert Hooke as one of the leading architects of the day, whom he already knew from work that Hooke had supervised on Jones' house in Bloomsbury. Hooke met Jones at least five times in 1681, and probably provided him with designs for Ramsbury Manor at that time. Construction of the house probably began in 1681, but the house was unfinished when Sir William Jones died in May 1682. The main structure of the house was completed in 1683, but work on the interior continued until 1686. The house is an excellent example of Hooke’s country house style or architecture, dignified and built to the best standards of the time.
In 1965 the house was sold with 460 acres of land to an American property dealer for £650,000; the Guinness Book of Records for 1966 described it as "the most expensive house in Britain".
Ramsbury Manor was the home of the property tycoon Harry Hyams until his death in 2015.
On 1 February 2006 the house was the scene of a major burglary by the Johnson Gang. The gang were caught and convicted; the prosecutor Paul Reid said: "This has been described as the most valuable domestic burglary ever committed in this country. The collection is described as priceless. There is a difficulty in putting a value on antiques and antiquities – some of them very precious and very rare – but it is tens of millions of pounds." In August 2008 the gang received long prison sentences.
It was announced in late December 2016 that Ramsbury Manor and the private and wide-ranging art collection of Harry Hyams was to be donated to the British nation, via the Capricorn Foundation. 
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- McGinty, Stephen (7 August 2008). "Family gang who stole £80m from 'lords and ladies' jailed for 49 years". Edinburgh: Scotsman.com.