Stokes' first reported job was to install TV antennas in Perth, followed by a sustained period in property development throughout the 1960s and 1970s. He also developed a range of shopping centres in Perth and regional Western Australia with partners Jack Bendat and Kevin Merifield.

Stokes's commercial interests in the media sector commenced in Western Australia, with the development of the Golden West Network, a regional television network based in Bunbury in partnership with Jack Bendat. In 1979 Stokes acquired Canberra's local TV station Seven Canberra, subsequently acquiring Seven Adelaide from Rupert Murdoch and won the TEN licence in Perth, as well as acquiring radio stations in Victoria, South Australia and Western Australia, through a vehicle called BDC. These assets were sold to Frank Lowy in 1987.

He invested in the Caterpillar franchise in Western Australia (Wigmores Ltd) in 1988, and the company now called WesTrac has equipment dealer franchises in Western Australia, New South Wales, the Australian Capital Territory and nine provinces across China, with the total number of employees close to 4,000 people, as well as 500 apprentices in Australia.

Stokes has been married four times. His first marriage was to Dorothy "Dot" Ebert, who is the mother of two of his children. In an interview with the Bulletin, it was implied that Stokes was estranged from his first family. His second marriage was to his receptionist, Denise, with whom he had two sons. Denise walked out of the marriage and went overseas, and Stokes became a single Father. His third marriage was to Australian television Actress Peta Toppano in 1992. This marriage lasted for three years. He is currently married to his fourth wife, Christine Simpson née Parker, who was a newsreader for rival station Channel 10 when they first met. He has three grandchildren, Bennett, Amelià, and Andrew Lukas Jack all fathered by son, Russell.

In 1995 Stokes was appointed an Officer of the Order of Australia (AO) for Service to Business and commerce to the arts and to the community. In 2008 Stokes was appointed as a Companion of the Order of Australia (AC) for Service to Business and commerce through strategic leadership and promotion of corporate social responsibility, to the arts through executive roles and philanthropy, and to the community, particularly through contributions to organisations supporting youth. His passionate interest in art coincides with his long association with the National Gallery of Australia, where he served as chairman for several years and has made multimillion-dollar donations.

In 1996 Stokes acquired a strategic 19 per cent stake in the Seven Network (now about 43 per cent), a network of commercial free-to-air television stations in Sydney, Melbourne, Brisbane and Adelaide, as well as regional Queensland & Perth. The platform, as well as a 33 per cent stake in Sky News Australia, now reaches 98 per cent of Australians. Seven has also established a major magazine publishing Business, Pacific Magazines, which now accounts for more than 20 per cent of all magazines sold in Australia.

John Patrick Alford was born in Melbourne, Australia and was adopted by Matthew and Irene Stokes. In June 2000, Stokes told the ABC, "My background was very difficult, very hard and I wouldn't wish that on anybody. I had lots of different occupations and obviously lots of different experiences. I had some time on the street, and sometimes, work was very difficult. Australia, in that period of time, wasn't a place where you could actually easily go and get a job, it was difficult, and we went where there was work available".

Stokes has taken an active role in preserving Australian ownership of significant military heritage; he has now purchased three Australian Victoria Cross medal sets, and a George Cross medal set. Stokes has purchased all four sets via auction from Bonhams & Goodman of Sydney, Australia. The first was the VC medal set of Captain Alfred John Shout, paying a world record price of A$1.2 million on 24 July 2006. In the same auction, he purchased the GC medal set of Lieutenant Commander George Gosse for A$180,000. On 28 November of the same year, Stokes purchased the VC set of Lance Corporal Bernard Gordon for A$478,000. He donated all three sets to the Australian War Memorial.

In 2007, Stokes' National Hire Group (over 50% owned by WesTrac) formed a joint venture with The Carlyle Group to acquire the equipment hire group Coates Hire.

On 20 May 2008, Stokes, in conjunction with the South Australian Government, purchased the Victoria Cross medal set of Major Peter Badcoe for A$480,000. The Badcoe medals were on public display in the South Australian Museum in Adelaide, and on tour in South Australia, for twelve months before going on display at the Australian War Memorial in Canberra.

In November 2012, Stokes was named Western Australia’s Australian of the Year for his extensive philanthropic contributions to Australian society. In 1994, Stokes delivered the Boyer Lectures, a series of five lectures broadcast annually on ABC radio. His series was entitled "Advance Australia Where?" on the topic of the Information Superhighway. He delivered the Andrew Olle Media Lecture in October 2001.

In 2014, the Business Review Weekly assessed Stokes' net worth at A$2.223 billion; making him the 14th richest individual Australian.

Stokes has always had a keen interest in the pastoral industry and acquired the 4,047 square kilometres (1,563 sq mi) Napier Downs station stocked with 20,000 head of Red Brahman cattle from Peter Leutenegger in 2015 for an estimated A$23 million to A$40 million.