Frédérique Bel made her acting debut in 2000 playing a small role in the comedy film Deuxième vie and later in the 2003 comedy film La Beuze. She then had famous supporting roles in comedy and romantic films. These include Tu vas rire, mais je te quitte in 2004, Imposture and The Russian Dolls in 2005. She portrayed Miss France in the 2006 science fiction comedy Un ticket pour l'espace and later featured in the comedy film Camping which had a box office of 5.5 million viewers. The same year, film Director Emmanuel Mouret gave her a role in his romantic comedy Change of Address, also featuring himself. She later featured in three other of his films, which are Shall We Kiss? in 2007, Fais-moi plaisir! in 2009, in which she appeared completely naked in one scene, and The Art of Love in 2011.

From 2001 to 2004, Frédérique Bel appeared in several television advertisements for various brands like Bouygues of Étienne Chatiliez, Darty of Yvan Attal, EDF of Jean-Pierre Jeunet, and also Mir Laine of Philippe Lioret where she portrayed the fairy. She later appeared in an advertisement for the optical brand Krys with other celebrities, including Alain Delon, Jane Birkin, Michel Blanc and Frédéric Beigbeder.

Frédérique Bel has also played in television films such as the 2006 mini-series Petits meurtres en famille, and later in the 2012 crime series Profilage, where she portrays a manipulating Lawyer until the end of the third season. To give the impression of a manipulating character, she even had to lower the tone of her voice to play the role. She had in between a supporting role in the sixth season of the historical fantasy series Kaamelott, where she portrayed Caesar's servant. She later had a regular role from 2011 to 2013 in the comedy series Fais pas ci, fais pas ça from the fourth to the sixth season. She also had a guest role in specials of television series Scènes de ménages in 2013 and Nos chers voisins in 2014. She played as Virginie Delome in the Netflix Original Series La Mante in 2017.

Frédérique Bel started a career as a voice Actress in 2007. Her shrill and particular voice, similar to a doll, gave her the opportunity to voice gentle female characters. She has since voiced in a number of animated films and series in both original and French versions. She began the same year in the third season of Canadian science fiction animated series Tripping the Rift, where she voiced the main character Six in the French version.

She then voiced Rose, the mother of Arthur, in the original versions of animated adventure films Arthur and the Revenge of Maltazard in 2009 and Arthur 3: The War of the Two Worlds in 2010, both directed by Luc Besson. In 2010, she voiced Barbie in the French version of Toy Story 3 and the same character the following year in Hawaiian Vacation, the first short film of the Toy Story Toons series.

Frédérique Bel has posted pictures and comments via social networks which caused a lot of controversy. In 2012 on her official Twitter account, while supporting François Hollande during the 2012 French presidential election, she was suspended after having posted pictures of her naked, only two days after having created her account. Her suspension was over three days later and she was allowed to post again on her account.

In 2013, she played one of the main roles in the romantic comedy Hôtel Normandy, filmed in the prestigious hotel Normandy Barrière located in the town of Deauville. In 2014, she portrayed one of the main characters in the comedy film Serial (Bad) Weddings with Christian Clavier and Chantal Lauby. The film was a huge success with a box office of over 200,000 viewers on its release date. She then featured the same year in the comedy-drama La Liste de mes envies, which was released soon after and is an adaptation from the novel of the same title, released in 2012.

In November 2014, her Facebook account was blocked for seven days for the head comment she posted on two articles she shared about trafficking of women in the Islamic State. She then used her Twitter account to express her anger of being censored by Facebook. She also added in an attached link the message she wrote them stating that she defends women's rights in the world and that she was angry for being blocked.