Raised in Den Haag and Voorburg, Mulder's father, Ben, is a tax inspector and her mother, Marijke, is a secretary. Mulder has a younger sister, Saskia, who became an actress after a stint studying economics. In 1985, her family went on a camping trip in the south of France. She saw an ad for Elite Model Management's "Look of the Year" contest in a newspaper. A friend took some photographs she had of her and sent them to Elite without her knowledge. She won the preliminary contest in Amsterdam, and was sent to the finals of the contest, placing second. She soon went to Paris for her first modeling shoot. She then left high school to travel to Italy with her mother for a formal photo shoot, and then to Paris for modeling school, where Elite took over her career.

By her second year on the runway, she was modeling for Valentino, Yves Saint Laurent, Lanvin, Versace, and Giorgio Armani. She appeared on the cover of Vogue and before long, landed a contract for Guess in 1991, when she was 21 years old. She soon appeared on the cover of British Vogue and in a Nivea advertising campaign. Other campaigns she appeared in included Calvin Klein, Claude Montana, Ralph Lauren, Yves Saint-Laurent's Rive Gauche fragrance, as well as Guerlain, Chloé, Revlon, Jacques Fath, Gianfranco Ferré, Gianni Versace, Chanel and Hervé Léger. Karen has worked with some of the greatest fashion photographers, including Javier Vallhonrat, Peter Lindbergh, Patrick Demarchelier, Bruce Weber, Helmut Newton, Max Vadukul, Gilles Bensimon, Fabrizio Ferri, Steven Meisel, Irving Penn, Robert Erdmann, and Arthur Elgort.

One of the first issues of Top Model magazine was entirely devoted to Mulder along with an entire issue of Italian Vogue. Her two appearances in the Sports Illustrated Swimsuit Issue in 1997 and 1998 and her poses for the Victoria's Secret catalogue increased Mulder's profile. Called "The Blonde With Class" by Vogue editors, she went on to share catwalks with models such as Kate Moss, Cindy Crawford, Claudia Schiffer, and Naomi Campbell. At one point in her career she was earning up to £10,000 a day. Mulder retired from modeling in 2000. Afterwards, she tried other career paths. She branched out into acting, making her debut in the French short film A Theft, One Night in 2001. She also pursued a career in music but had limited success. Her first effort at establishing a music career was her cover version of Gloria Gaynor's "I Am What I Am", which appeared on the French music charts for a time in the summer of 2002.

• Village des enfoirés, Le (2006) (TV) .... Herself
• Train des enfoirés, Le (2005) (TV) .... Herself
• "20h10 pétantes" .... Herself (1 episode, 2004)
  ... aka 19h10 pétantes (France: new title)
  ... aka 19h10 pétantes à Cannes (France: festival title)
  ... aka 19h20 pétantes à Bourges (France: festival title)
  ... aka Samedi pétantes (France: third season title)
  ... aka Vendredi pétantes (France: third season title)
       - Episode dated 22 June 2004 (2004) TV episode .... Herself
• "Tout le monde en parle" .... Herself (2 episodes, 2002-2004)
       - Episode dated 29 May 2004 (2004) TV episode .... Herself
       - Episode dated 8 June 2002 (2002) TV episode .... Herself
• 2001 - l'odyssée des enfoirés (2001) (TV) .... Herself
• Stars and Bras (2000) (TV) .... Herself
• Enfoirés en 2000 (2000) (V) .... Herself
  
• Enfoirés: dernière édition avant l'an 2000, Les (1999) (V) .... Herself
• Enfoirés en coeur (1998) (V) .... Herself
• Sports Illustrated: Swimsuit '97 (1997) (TV) .... Herself
• Die Schönsten Frauen der Welt - Karen Mulder (1995) (TV) .... Herself
• Die Schönsten Frauen der Welt - Carla Bruni (1995) (TV) .... Herself
• Unzipped (1995) (uncredited) .... Herself