[3][12] In her sophomore year at high school, she received a call from a local clothing store regarding modeling work, only to discover it was a prank by two of her classmates.

[14][16] She earned an academic scholarship to study chemical engineering at Northwestern University, which she attended for only one quarter before dropping out to pursue a full-time modeling career.

Three years later, she was featured alongside top models Christy Turlington, Linda Evangelista, Tatjana Patitz and Naomi Campbell on the cover of the January 1990 edition of British Vogue.

Subsequently, Crawford played the lost love of Jon Bon Jovi in the 1994 video for his version of "Please Come Home For Christmas", "John Taylor" in the 2011 video for Duran Duran's "Girl Panic" (featuring supermodels as the band, including Naomi Campbell as Simon Le Bon), and Headmistress in the 2015 video for Taylor Swift's "Bad Blood" as part of a cast including Jessica Alba, Selena Gomez, and fellow models Lily Aldridge, Cara Delevingne, Gigi Hadid, Martha Hunt and Karlie Kloss.She was frequently featured on the cover of multiple fashion and lifestyle magazines, including Vogue, W, People, Harper's Bazaar, Elle, Cosmopolitan, and Allure.

[20] Crawford has walked the runway shows for Chanel, Versace, Dolce & Gabbana, Christian Dior, Calvin Klein, Ralph Lauren, Roberto Cavalli, Michael Kors, Thierry Mugler, Todd Oldham, DKNY, and Valentino.

Crawford also appeared in many fashion campaigns during her career, including those for Versace, Calvin Klein, Escada, David Yurman, Oscar De La Renta, Balmain, Hermes, Ellen Tracy, Valentino, Bally, Liz Claiborne, Hervé Leger, Halston, Anne Klein, Isaac Mizrahi, Blumarine, Guess, Ink, Gap, and Revlon.

For example, in 2000, she was one of the celebrities (along with Victoria Silvstedt, Anna Falchi and Megan Gale) playing themselves in the Italian comedy Body Guards – Guardie del corpo.

In the 1990s, Carol Shaw, her make-up artist, named a lipstick color after Crawford as a part of the Lorac Cosmetics lip-wear line.

On a number of occasions, she joined Copperfield and Schiffer in a performance of the Double Sawing illusion in which both women were sawn in half and then reassembled with their lower halves swapped.

The collection is manufactured by HM Richards Inc. She assisted in the creation of the line by consulting on the features, colors, or styles that fit the needs of families or reflected her own tastes.

[38] In 2009, Crawford was one of many celebrities to be photographed by Deborah Anderson for the coffee table book Room 23, produced by philanthropist Diana Jenkins.

[40] Crawford appeared on the US version of Lipsync Battle reenacting her performance in the bathtub from the George Michael music for "Freedom!

[43] In January 2019, Crawford, along with her husband Rande Gerber, Michael Meldman, Jeff Shell, and Jay Sures announced they would purchase the Hollywood deli, Nate 'n Al, to keep its doors open after three generations of family ownership.

The series also featured Naomi Campbell, Christy Turlington, and Linda Evangelista and was directed by Roger Ross Williams and Larissa Bills.

[54][55] When Crawford was 10 years old, her three-year-old brother Jeff—whom she continues to praise as "the fourth most influential person in [her] life"—died of leukemia.

Since becoming a model, Crawford has made childhood leukemia a focal point of her charity work, donating proceeds of her calendars to medical research.

[56] Crawford has been a long-time supporter of the pediatric oncology program at the University of Wisconsin–Madison, where Jeff was treated, stating that she believes he received the best care possible.

[58] In 2007, she became an official supporter of the Ronald McDonald House Charities and is a member of their celebrity board, called the Friends of RMHC.

[60] In 2021, Cindy Crawford recreated her iconic Pepsi ad with photographer David Yarrow to help raise funds for the American family Children's Hospital in Madison, Wisconsin where her brother, Jeff, was treated for leukemia.