In 1998, Tautou participated in a Star Search-like competition sponsored by Canal+ called "Jeunes Premiers" (The Young Debut) and won Best Young Actress at the 9th Béziers Festival of Young Actors. Tonie Marshall gave her a role in the César-winning Venus Beauty Institute (1999, aka Vénus beauté (institut)). In 2000, she won the Prix Suzanne Bianchetti as her country's most promising young film actress.
In 2001, Tautou rose to international fame for her performance as the eccentric lead in the romantic comedy Le Fabuleux Destin d'Amélie Poulain (Amélie). In June 2004, she was invited to join the Academy of Motion Picture Arts and Sciences (AMPAS).
In 2005, Tautou worked in her first full Hollywood production, opposite Tom Hanks, in the film version of Dan Brown's best-selling novel The Da Vinci Code, directed by Ron Howard and released in May 2006. She acted alongside Gad Elmaleh in Pierre Salvadori's Hors de prix (Priceless), released 13 December 2006. The film has been compared to Breakfast at Tiffany's.
Tautou starred with Guillaume Canet in Claude Berri's Ensemble, c'est tout in 2007, an adaptation of the eponymous novel by Anna Gavalda.
Tautou played the lead role in the biopic of fashion designer Coco Chanel, titled Coco avant Chanel, and directed by Anne Fontaine. Filming began in Paris in September 2008, and released in France on 22 April 2009. The script is partially based on Edmonde Charles-Roux’s book “L’Irrégulière” (”The Non-Conformist”). As part of promoting the film, Tautou was named as the next spokesmodel for Chanel No. 5, replacing Nicole Kidman. She was directed in the advertisement by Jean-Pierre Jeunet, with whom she worked on Amélie and A Very Long Engagement. The advertisement was released in 2009 to coincide with the film's release. She has also modeled for magazines such as Vogue, Elle and Harpers Bazaar, Marie Claire, and lent her face to L'Oreal and Montblanc ad campaigns.
She appeared in the video of "I Love Your Smile", a song by British singer-songwriter Charlie Winston.