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Mayfair was mainly open fields until development started in the Shepherd Market area around 1686 to accommodate the May Fair that had moved from Haymarket in St James's. There were some buildings before 1686 - a cottage in Stanhope Row, dating from 1618, which was destroyed in the Blitz in late 1940, though there is no evidence of meaningful habitation or building before 1686. There has been speculation that the Romans settled in the area before establishing Londinium. A theory has been proposed since the 1950s that Aulus Plautius set up a fort near the junction of Park Street and Oxford Street during the Roman conquest of Britain in AD 43 while waiting for Claudius; the theory was more fully developed in 1993, with a proposal that around the fort a Roman town formed, which was later abandoned as being too far from the Thames. The proposal has been disputed due to lack of archaeological evidence. If there was a fort, it is believed the perimeter would have been where the modern roads Green Street, North Audley Street, Upper Grosvenor Street and Park Lane now are, and that Park Street would have been the main road through the centre.

Sir Thomas Grosvenor, 3rd Baronet married Mary Davis, heiress to part of the Manor of Ebury, in 1677; the Grosvenor family gained 40 hectares (100 acres) of Mayfair. Most of the Mayfair area was built during the mid 17th century to mid 18th century as a fashionable residential district, by a number of landlords, the most important of them being the Grosvenor family, which in 1874 became the Dukes of Westminster. In 1724 Mayfair became part of the new parish of St George Hanover Square, which stretched to Bond Street in the south part of Mayfair and almost to Regent Street north of Conduit Street. The northern boundary was Oxford Street and the southern boundary fell short of Piccadilly. The parish continued west of Mayfair into Hyde Park and then south to include Belgravia and other areas. In the 19th century the Rothschild family bought up large areas of Mayfair. The freehold of a large section of Mayfair also belongs to the Crown Estate.

The district is now mainly commercial, with many offices in converted houses and new buildings, including major corporate headquarters, a concentration of hedge funds, real estate businesses and many different embassy offices, namely the large US consulate taking up all the west side of Grosvenor Square. Rents are among the highest in London and the world. There remains a substantial quantity of residential property as well as some exclusive shopping and London's largest concentration of luxury hotels and many restaurants. Buildings in Mayfair include the United States embassy and the former Canadian High Commission in Grosvenor Square, the Italian Embassy, the Royal Academy of Arts, the Handel House Museum, the Grosvenor House Hotel, Claridge's and The Dorchester.

Mayfair is home to many museums and galleries, including the Handel House Museum, Faraday Museum, the Fine Art Society gallery, and Halcyon Gallery.