In 1993, Kruger represented Germany in the Elite Model Look and started modelling afterwards. Despite her relatively short stature for a model, she managed to land bookings such as advertisements from Yves Saint Laurent, Chanel, Salvatore Ferragamo, Giorgio Armani, Jil Sander, Christian Dior, Burberry and Louis Vuitton; runway shows from Marc Jacobs, D&G and Sonia Rykiel as well as appearances on the cover of Vogue Paris, Marie Claire and Cosmopolitan to her modeling repertoire. She gradually stopped modelling after deciding to pursue a career in acting.

Kruger became interested in acting and took lessons at the Cours Florent. She made her film debut in 2002, opposite Dennis Hopper and Christopher Lambert in The Piano Player, a TV film by Jean-Pierre Roux. The same year, she also starred in her then husband’s directorial début Mon Idole.

She played Julie Wood in 2003’s Michel Valliant and Lisa in Wicker Park (2004), alongside Josh Hartnett and Rose Byrne. One of her more high-profile roles to date is her portrayal of Helen of Sparta in Wolfgang Petersen’s epic Troy. She was ranked 50th on the Maxim Hot 100 Women of 2005. In 2004, Kruger starred with Nicolas Cage and Sean Bean (who co-starred with her in Troy) in the film National Treasure, going on to appear in films Joyeux Noël (2005), and Copying Beethoven (2006). She reprised her role as Dr. Abigail Chase in National Treasure: Book of Secrets, released in December 2007.

Kruger was the hostess of the opening and closing ceremonies of the 2007 Cannes Film Festival. Kruger was a jury member of the 58th Berlin International Film Festival in 2008. The festival is chaired by Costa Gavras.

In 2009, she co-starred as a German actress turned Allied spy in Quentin Tarantino’s film Inglourious Basterds. In December 2009, she announced the nominations of the 67th Golden Globe Awards and also picked up nominations from the Screen Actors’ Guild for Best Supporting Actress and Outstanding Performance by a Cast of a Motion Picture for her role in Inglourious Basterds.

Kruger is a brand ambassador for Swiss watch manufacturer Jaeger-LeCoultre. In December 2009, she was announced as the global “spokesmodel” of L’Oréal. It was announced in May 2010 that she would become the latest face for Calvin Klein’s newest fragrance line, Beauty.

Kruger played Anna in Jaco Van Dormael’s Mr. Nobody. Critical response has praised the film’s artistry and Kruger’s acting. Kruger made a cameo appearance in an April 2010 episode of the Fox show Fringe, in which her former boyfriend, actor Joshua Jackson, starred. In 2010, Kruger also appeared in Mark Ronson’s music video for “Somebody to Love Me”, where she plays Boy George.

In the 2011 film Unknown, Kruger starred as Gina, a Bosnian illegal immigrant, and key character alongside leading actor Liam Neeson. It was also announced in 2011 that Kruger had replaced Eva Green in the role of Marie Antoinette in the French-language film, Les Adieux à la Reine. In 2012, she was named as a member of the Jury for the Main Competition at the 2012 Cannes Film Festival. The festival is chaired by Nanni Moretti. She starred in the film adaptation of Stephenie Meyer’s novel The Host, which was released in March 2013. More recently, Kruger portrayed El Paso, Texas, police officer Sonya Cross on FX’s The Bridge, which aired in 2013. In 2015, she was named as a member of the Jury for the Main Competition at the 2015 Venice Film Festival. In 2016, she co-starred in The Infiltrator with Bryan Cranston and John Leguizamo. In 2019, Kruger replaced Marion Cotillard in the spy movie The 355.

Kruger is fluent in German, English, and French. In 2013, she became an American citizen. In 1999, she began dating the French actor and director Guillaume Canet. They were married on 1 September 2001. They acted together in Joyeux Noël (2005) and divorced in 2006. Kruger said that the marriage was unsuccessful because their careers had kept them in different parts of the world. She dated actor Joshua Jackson from 2006 to 2016.

During the production of the film Sky, in 2015, Kruger met her co-star for that film, Norman Reedus. The two were first seen together as a couple in July 2016. In November 2018, Kruger gave birth to their daughter, her first and his second child.