Desmarais took control of his family's bus service, Sudbury Bus Lines, in 1951. He then acquired additional bus lines in the Ottawa area and Quebec City (including Quebec Autobus and Provincial Transport). By 1968, Desmarais's holding company, Trans-Canada Corporation Fund (TCCF), owned the bus line Provincial Transport, an interest in Toronto-based Imperial Life Assurance and Gesca Ltée, (which had an interest in the Montreal paper La Presse). That year TCCF made a share-exchange offer with Power Corporation of Canada, headquartered in Montreal, Quebec, whereby Paul Desmarais became Chairman and Chief Executive Officer.

Desmarais' Power Corporation of Canada owns about 15% of Groupe Bruxelles Lambert, a Belgian holding company, which in 2001 acquired a 25% interest in the German media company Bertelsmann, whose subsidiaries include BMG and Random House. Groupe Bruxelles Lambert owns 3.7% of the French oil conglomerate Total. Desmarais has been accused of having close business ties with Saddam Hussein, which Desmarais has refuted. Total made a deal with Saddam giving it exploration rights to 25% of Iraq's oil reserves.

In 1974, Desmarais named employee Paul Martin, Jr. as president of a Power Corporation subsidiary, Canada Steamship Lines Inc. In 1981, he sold the company to Laurence Pathy and Paul Martin, Jr. The latter became Prime Minister of Canada on December 12, 2003. In 1978 he was made an Officer of the Order of Canada and was promoted to Companion in 1986. Desmarais is a staunch opponent of the Quebec sovereignty movement.

Paul Desmarais sits on the advisory board of the Carlyle Group.

Desmarais has two sons: Paul Jr. and André (who is married to former Canadian Prime Minister Jean Chrétien's daughter France) and two daughters, Sophie and Louise.