During the early half of the 20th century, the Royal Victoria Dock became an essential part of industrial Britain and London’s largest centre of flour milling. Vernon & Sons were the last to set up in 1905 when they built The Millennium Mills which is now now derelict. These mills converted imported grain from overseas into flour for the London market and were the first in the Port of London designed to take imported grain direct from the ships.

The mills were extensive, featuring two plants, equipped by Henry Simon Ltd, that had a capacity of 100 sacks per hour. Vernon and Sons named the mill after their most successful product, a flour variety which they called "Millennium Flour" after winning the "The Miller Challenge Cup" at the 1899 International Bakers Exhibition.

All of these mills were partially destroyed in 1917 by the Silvertown explosion at Brunner Mond's munitions factory on the North Woolwich Road that was manufacturing explosives for Britain's World War I military effort. The Brunner Mond 
works was about 100 yards east of where Millennium Mills stood, and the adjoining grain silos and flour warehouses were amongst the 17 acres of buildings that the Port of London Authority estimated were affected.

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In 1920, Vernon & Sons was taken over by Spillers Limited at which time the Millennium Mills was acquired. Spillers was an established flour milling business founded in 1829, which subsequently went into the production of dog food and animal feeds by 1927. The Spillers name remains prominent on the east and west wings of the building.

Millennium Mills was rebuilt as a 10-storey concrete art deco building in 1933.

Many port mills throughout the country sustained severe damage from bombing in the Second World War; almost 75 per cent of the national capacity was concentrated at the ports, which made them primary targets for air attacks. In London, Spillers' Millennium Mills as well as Rank's Premier Mills were substantially destroyed. Between 1945 and 1950 the ports underwent large-scale post-war reconstruction despite a deficit of raw materials and strict licensing. At this time Millennium Mills was rebuilt, including a windowless steel-framed infill on the west side, and was in operation by September 1953.

The Royal Docks closed in 1981, and many businesses relocated to Tilbury. The London Docklands Development Corporation (LDDC) was in discussion in the 1990s with the Zoological Society of London for a public aquarium on the site of the former CWS mill, but funding for it was difficult to find and the idea was eventually shelved. The Rank and CWS mills were demolished by the LDDC in the 1990s, along with the Millennium Mills' B and C silos. The D silo to the south is Grade II listed. Millennium Mills itself is locally listed by Newham Council.

In 2001 a project was proposed for the redevelopment of the former docklands area with a planning request being submitted to the Local Authority in 2003. By 2007, a £1.5 billion building scheme had been approved to convert the 24 hectares (59 acres) site into a mixed use development with residential, commercial, leisure and public areas. It was estimated that the scheme would be one of the largest urban regeneration projects in Europe, creating 2,000 jobs.

The scheme was set to deliver 4,900 waterfront homes, with the intention of converting the Mills themselves into 400 luxury loft-style flats called Silvertown Quays. The development was also to include a new aquarium for London called 
Biota!, designed by Terry Farrell and Partners. The building scheme was supported by a partnership between the landowner, the London Development Agency (LDA), joint developers Silvertown Quays Limited (SQL) and the Japanese developer Kajima Urban Development International with financial backing by the Bank of Scotland. The first phase of the redevelopment was to see the Millennium Mills building developed into flats, with the demolition of the eastern and western wings, including the remains of the Rank Premier mill, leaving the main block of Millennium Mills, plus the south-western extension as a standalone tower. Planning approval was granted in 2007. However, no date was decided for work to commence.

In 2009, the LDA, having seen no progress on the project, served termination notices to the SQL, setting a deadline of the February 13, 2010 for the company to secure sufficient funds for the project. When the termination notice expired and the funds were unable to be raised the LDA ended their agreements with the SQL and the Silvertown Quays development was officially cancelled. Despite discussion with SQL’s main backer, the Bank of Scotland, and a new plan and revised timetable for the regeneration of the site, the London Development Agency concluded that it could not accept the new proposals. Architects Journal suggested that the area could be incorporated into a larger masterplan for the docks as part of a wider Royal Docks masterplan housing up to 30,000 people.

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Around 2011, the building remained derelict and was a destination for Urban Explorers who enter the site at high risk. There are many reports and internal photos of the site in this state.

The Millennium Mills and Silo D site area was redeveloped as the London Pleasure Gardens and opened in 2012 to coincide with the London Olympics. Due to remain open for 3 years hosting music and arts events, the site encountered difficulties from its initial opening with negative reviews labelling the site as unfinished and unsafe with some of the advertised buildings absent and the area mostly devoid of greenery. Later events such as the Bloc Festival suffered from overcrowding and the planned number of visitors coming from the ExCel Centre during the London 2012 Olympics never materialized. 
The site subsequently went into administration after only 5 weeks costing Newham council £4 million.

On 21 April 2015, Newham Council gave planning permission to The Silvertown Partnership for a new £3.5billion redevelopment of the area, including Millennium Mills. The building will become a centre for start-up businesses. Part of Pontoon Dock itself will be filled in so that the land can be developed.

Work began in January 2015 to clear the building of asbestos, following an initial £12 million grant from the government. To mark the grant, communities minister Penny Mordaunt MP and the deputy mayor of London for housing, Richard Blakeway, paid a visit to the 62 acre site.

Speaking on the site, Penny Mordaunt MP said “There will be a lot of people working here who will be able to live in the area. This iconic building will be the centrepiece of a thriving new business district that will create thousands of new jobs and bring prosperity back to the docks.” 

The then Mayor of London Boris Johnson said of the renovation: "The restoration of this great industrial monolith is another vital ingredient in the regeneration of London's historic Royal Docks. We want to return this site to its former glory, supporting business and enterprise and breathing new life into an area of the capital that has been dormant for decades."

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In September 2015, the mills were open to the public as part of the Open House London weekend in which visitors were able to tour the sixth floor of the East wing, tenth floor of the main building, the East roof top and the Rank Hovis mill. 
As of September 2015, the Millennium Mills have been cleared of internal machinery and grain chutes which posed an asbestos risk, though the removed artifacts are planned to be donated to artists to use. A two storey pavilion on the roof is planned to be removed to make way for a rooftop bar and restaurant. The concrete East wing stub is planned to be demolished as well as large parts of the south facing fall being removed and replaced. Plans to redeveloped the adjacent Rank Hovis mill are not currently finalised due to its higher rate of decay and architectural significance.