He studied business at the University of Münster and received his doctorate at the Institute for Marketing under the supervision of Heribert Meffert.

In 1986 he moved to Bertelsmann, a multinational media corporation based in Germany, as assistant manager of the graphic firm in Gütersloh.

In 1994 he was appointed to the Executive Board of Bertelsmann AG and took over management of corporate development and coordination of the multimedia business, where he was responsible for the strategic realignment of the group in the field of electronic entertainment.

During this time he built up the RTL Group, today the largest operator of advertising-financed commercial television and radio in Europe.

In addition, he was responsible for a planned joint venture with Amazon, which did not receive the approval of the majority on Bertelsmann's Executive Board.

Middelhoff pushed through the renaming of KarstadtQuelle as Arcandor and divided the operational business into the three core areas of department store (Karstadt), mail order (Primondo) and tourism (Thomas Cook).

Since 2007, Middelhoff was Chairman of the Supervisory Board of the Thomas Cook Group, the world's second largest tourism company, in which Arcandor held 52% of the shares.

On the same day, it became known that the responsible public prosecutor's office had opened a preliminary investigation into Middelhoff's personal involvement in the Oppenheim-Esch Fund, this going back to the suggestion of the then Federal Minister of Justice Brigitte Zypries (SPD), with a corresponding letter & request to former counterpart Roswitha Müller-Piepenkötter (CDU) to intervene, which was then discontinued years later.

[13] In 2014, Middelhoff was convicted on criminal charges related to his activities while head of Arcandor; he was sentenced to three years' imprisonment.

In 2010, Germany1 was renamed 3W Power Holdings, the company headquarters were relocated from the British tax haven of Guernsey to Luxembourg, and Middelhoff was elected to the Board of Directors.

On October 20, 2017, the Stuttgart Regional Court granted an injunction by the news magazine Der Spiegel, so that the book in its original version written by Middelhoff could no longer be sold.

Middelhoff claimed in the book that the editors of Der Spiegel had researched improperly, withheld facts and relied on dubious sources.

[20] On November 23, 2017, the documentary People Up Close: Thomas Middelhoff – Crash of a Top Manager was broadcast on WDR.