[7] Following her high school graduation, Janssen studied economics for a year at the University of Amsterdam, which she later called "the stupidest idea I ever had.

She signed with Elite Model Management and worked for Yves Saint Laurent, Giorgio Armani, Chanel, and Victoria's Secret.

In 1995, Janssen appeared in Pierce Brosnan's debut James Bond film, GoldenEye, as femme fatale Xenia Onatopp.

In an attempt to fight against typecasting after her Bond girl performance, Janssen began seeking out more intriguing support roles, appearing in John Irvin's City of Industry, Woody Allen's Celebrity, Robert Altman's The Gingerbread Man, and Ted Demme's Monument Ave.[12] Denis Leary, her co-star in Monument Ave., was impressed by how easily she blended in, initially not recognizing her, as she was already in character.

She later reprised the role in the 2003 sequel, X2, where her character shows signs of increasing powers, but at the end of the film, she is presumably killed.

[15][16] In 2002, Janssen landed the role of villainess Serleena in Men in Black II, but had to abandon the film due to a death in her family and was replaced by Lara Flynn Boyle.

Janssen continued to work in television, appearing in TV pilots for NBC's police drama Winters and Showtime's The Farm, a spinoff of The L Word set in a women's prison.

Janssen starred in the Netflix original horror thriller television series Hemlock Grove, wherein she plays the role of family matriarch Olivia Godfrey.

[28] In a March 2021 interview, she revealed to Forbes some details about her involvement with the live action adaptation of Saint Seiya, a popular anime and manga.

Janssen declared that filming was supposed to take place in Europe the previous year, but production had been postponed twice due to the Coronavirus pandemic.

[29] Janssen appeared with her dog, Licorice, a brindle Boston Terrier, in a 2007 PETA campaign to raise awareness for animal rights.