Crawford quit full-time modeling in 2000 and now appears only occasionally in fashion magazines. She continues to provide celebrity endorsement for a variety of projects. In 2005, Crawford created a line of beauty products with Jean-Louis Sebagh called Meaningful Beauty for Guthy-Renker. Crawford has stated that she regularly receives certain cosmetic procedures, including Botox and vitamin injections. She first saw a plastic surgeon at the age of 28.

In 2005, Crawford launched a new line of furniture under the "Cindy Crawford Home Collection" name. 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. She also has a furniture line with Raymour & Flanigan and launched a home goods line with J. C. Penney in late 2009.

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. In addition to appearing in the book, Crawford was the cover model and wrote the dedication.

Crawford returned to modeling in May 2011, appearing on the cover of the May 2011 issue of Vogue Mexico.

In 2014, Crawford lead a rally promoting environmental safety at Malibu schools. The Malibu Times states that several Malibu teachers came forward with health issues in October 2013, including three with thyroid cancer. Toxic soils were reportedly found at Malibu High in 2010, with the school district failing to inform parents about the problem.

Becoming, a book about Crawford's life and career co-written by Crawford and Katherine O'Leary, was published in September 2015.

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. 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. She is also an honorary board member of the Multiple Myeloma Research Foundation.

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.Crawford is on the honorary committee of the California Wildlife Center.