The family had previously fled Upper Silesia and settled in Kulmbach in Franconia. Gottschalk became an altar boy in the town parish church here. After completing school with a high school diploma at the Humanistic High School in Kulmbach, he studied German and history to become a primary and secondary school teacher in Munich. From 1971 Gottschalk worked as a freelancer for Bayerischer Rundfunk. As a permanent employee there, from 1976 to 1989 he moderated, among other things, the radio program "Pop after eight" and "Thommy's Radio Show" as well as the "Scene program" of the third TV program. During this time, in 1976, Gottschalk married his childhood friend Thea. This relationship resulted in son Roman and adopted son Tristan. In 1977 he first became known to a large TV audience as the host of the game show "Telespiele" produced by the SWF in Baden-Baden. After further success, Gottschalk moved to ZDF in 1982, where he accompanied the program "Na so was" for a total of four years. During this time he already celebrated his first successes as an actor in humorous entertainment films. Together with his colleague Mike Krüger he was seen in films such as "Piratensender Powerplay" and "Die Supernasen".

For "Oh well!" In 1983 he was awarded the "Golden Gong" and in 1985 he received the "Golden Camera". In 1986, Thomas Gottschalk took over as presenter of the ZDF show "Wetten Dass...?", succeeding Frank Elstner. The show first aired in 1981. The new presenter made the program the most successful Saturday evening show in Europe with up to 15 million viewers. The content of the program was spectacular bets that were placed against the mostly world-famous star guests. Gottschalk was quickly accepted as the new presenter and, after a two-year break (1992-1994), introduced the successful concept "Wetten Dass...?" continued. From 1990 Gottschalk also worked for RTL. He hosted the weekly personality show "Gottschalk" until 1992 and hosted the "Gottschalk Late Night Show" until 1995. He then moved to SAT.1, where he hosted "Gottschalk's House Party" from 1995 to 1997 and, from September 1998, the weekly show "Gottschalk comes!" moderated. Meanwhile, Gottschalk also appeared in numerous cinema productions as an actor. These include "Tender Chaoten" (1987), "A Woman Called Harry" (1990), "Trabbi Goes to Hollywood (1991) and "Sister Act 2" from 1994 alongside Whoopi Goldberg.

These works, especially the professional sequel to "Wetten Dass...?", made Gottschalk, an American by choice who settled in Malibu with his family in the early 1990s, into the most successful German talk show host. In November 1999 he was chosen for his show "Wetten, dass...?" awarded the German Television Prize. He also appeared in front of the camera alongside Harald Schmidt in the 1998 film comedy "Late Show", directed by Helmut Dietl. In addition to numerous advertising appearances for HARIBO and McDonald's, Gottschalk and his brother Christoph also became active in advertising for Deutsche Post AG. In November 2003 it was announced that Gottschalk would host the ZDF show "50 Years of Rock Music" in April 2004 as well as a ZDF documentary about the Hollywood director Wolfgang Petersen. Gottschalk appeared as a voice actor in various films such as "In Tierischer Mission" (2003). He also lent his voice to the animated cat "Garfield" in the film of the same name. The production was released in German cinemas in August 2004. Also in August 2004, a biography about Gottschalk by Gert Heidenreich was published under the title "Thomas Gottschalk".

On October 2, 2004, Gottschalk moderated the 150th edition of the "Wetten,dass...?" show on ZDF. In the 23-year history of the format, 102 issues alone have been credited to Gottschalk. At the end of 2004, Gottschalk bought Marienfels Castle near Remagen on the Rhine, which he lived in from 2006. In February 2005, Gottschalk was named "best international showmaster" for his ZDF show "Wetten, dass...?" nominated for the Golden Rose of Lucerne. At the beginning of May 2005 he was awarded the Golden Rose as best game show host at the Rose d'Or (Golden Rose) television festival in Lucerne. On August 28, 2005 and August 26, 2006, he hosted the program "The Cleverest - The Big Three-Country Check", in which teams from the three German-speaking countries of Germany, Austria and Switzerland compete against each other. Between 2000 and 2005, ZDF broadcast ten episodes of "Gottschalk America". In April 2008 he hosted the show "Musical Showstar 2008". In 2008 he was also seen alongside Till Schweiger in the cinema production "1½ Ritter - In Search of the Adorable Herzelinde".

From October 3, 2009, Gottschalk moderated the show "Wetten Dass...?" together with Michelle Hunziker. In 2009 he had a guest appearance in the 895th episode of the TV series "Storm of Love". In the same year he played in the 60th episode of "Das Traumschiff". At the beginning of the 192nd "Wetten, dass?..." broadcast on December 4, 2010, the betting candidate Samuel Koch was dramatically injured. The live broadcast was then canceled. As a result, Gottschalk announced his resignation as presenter of the show. After the 151st edition on December 3rd, 2011, Markus Lanz took over the show. In 2019, Thomas and Thea Gottschalk's separation became public. Meanwhile, he settled in Baden-Baden, where his relationship with Karina Mroß became known. From 2020 to 2021 he could be heard with the radio presenter Nicola Müntefering on the fortnightly SWR3 podcast Podschalk and from May 2020 he hosted the radio show "Gottschalks Playlist" every second Friday. On November 6, 2021, ZDF broadcast a revival edition of "Wetten,dass?", which achieved a market share of 45 percent.