He started his business in 1863 by opening a Fancy Goods shop at 31 Westbourne Grove, employing two girls to serve and a boy to run errands.

Whiteley's met strong opposition from smaller tradesmen, and also from the local authorities over its grand building plans, and several bad fires in the 1880s may have been caused by opponents.

Business nonetheless prospered, aided by a delivery service extending up to 25 miles (40 km), and in 1887 the store was described as 'an immense symposium of the arts and industries of the nation and of the world'.

By 1890 over 6,000 staff were employed in the business, most of them living in company-owned male and female dormitories, having to obey 176 rules and working 7 am to 11 pm, six days a week.

In his autobiography, Drawn From Memory, E. H. Shepard said the fire could be seen from Highgate Hill, and some days later when he and his brother Cyril were allowed to visit Westbourne Grove, that, "The long front of the shop was a sorry sight with part of the wall fallen and the rest blackened."

When the Lord Mayor of London in the presence of thousands opened the new store in Queensway on 21 November 1911, it was claimed to be the largest shop in the world.

After his death, the board including two of Whiteley's sons allowed the leases on the various Westbourne Grove properties to lapse and moved into a new purpose built store on Queens Road (now called Queensway).