In 1999, he joined J&T as lawyer and became a partner in 2003. Since 2004 he is chairman of football club AC Sparta Prague and he is believed to be its 40% shareholder.

When in 2009 J&T founded Energetický a průmyslový holding, he became its chairman and 20% shareholder. He ceased to be a partner of J&T. In 2011, he became chairman and 60% shareholder of EP Industries, that was divested from EPH. In 2016, he took 94% ownership of EPH through a series of transactions including EPH’s sale of a 30% stake in subsidiary EPIF where the proceeds were used to buy out other shareholders.

From 2014, he is one of the owners of Czech media house Czech News Center, among others publisher of tabloid Blesk, the most read newspaper in the Czech Republic.

In October 2018, staff at Le Monde learned that Křetínský had purchased 49% of Matthieu Pigasse’s stake in the company. Le Monde’s Independency Group, a minority shareholder that aims to protect the paper’s editorial independence, had not been informed of the sale, and asked Pigasse and Křetínský to sign an “approval agreement” that would give the Independency Group the right to approve or reject any controlling shareholder. As of September 2019, they had not done so.

On 12 March 2020, Jérôme Lefilliâtre, a French journalist, published Mister K, Petites et grandes affaires de Daniel Kretinsky (Le Seuil Editions), an investigative book about the Czech billionaire.

On 16 September 2020, his holding company Vesa Equity Investment Sarl announced a 3.05% holding interest in the shares of J Sainsbury plc, a major supermarket chain in the United Kingdom.

On 30 March 2020, he announced that he had tested positive for coronavirus disease 2019, so far the highest profile person to be infected during the 2020 coronavirus epidemic in the Czech Republic.