[12] In 2006, at the age of 14, she posed for the photographer David Leslie Anthony in a cover and editorial spread titled "Almost Famous," for the June issue of Scene Magazine.

[39] Kloss made her first venture into television when she appeared in the Gossip Girl episode "Belles de Jour" as herself.

[53] She appeared in campaign ads for Juicy Couture,[54] Stefanel,[55] Elie Saab,[56] and Jean Paul Gaultier.

[59] Just before appearing in the Victoria's Secret Fashion Show in 2012, Kloss had her long hair cut into a bob, which was subsequently called the "Karlie".

[60][61] One of her outfits was cut out of the Victoria's Secret broadcast as it contained a Native American headdress that was deemed offensive.

[64] In April, Kloss starred alongside Daria Strokous, Monika Jagaciak, and Iris Strubegger in Louis Vuitton's Alma bag campaign.

[67] Kloss was the face of Jean Paul Gaultier, Nike, Donna Karan, Lancaster, and the Chanel Coco Noir fragrance campaigns in 2014.

[74] Kloss also featured in several video segments during Swift's 1989 World Tour[75][76] and appeared live on stage with her at London's Hyde Park on June 27[77] and at the MetLife Stadium in East Rutherford, New Jersey on July 11.

[78] In March 2015, Kloss starred in the music video for Chic's "I'll Be There", directed by Inez van Lamsweerde and Vinoodh Matadin.

[79] On July 21, 2015, she started a YouTube channel, Klossy,[80] featuring weekly vlogs and Q&A videos, with help from her close friend, filmmaker Casey Neistat.

[81] In May 2016, Kloss was named the new face of Swarovski for a two-year contract, replacing fellow Victoria's Secret alumna Miranda Kerr.

[84] Kloss was featured in Vogue's March 2017 issue styled as a geisha[85] and received criticism for cultural appropriation;[85][86] she posted a public apology for the spread.

[91] In October 2018, Kloss confirmed that she would be stepping into Heidi Klum's shoes on the seventeenth season of Project Runway as the host and executive producer.

Of the show, she said, "I could not be more excited to host and produce a series that provides a platform to aspiring American designers as they pursue their creative and entrepreneurial dreams.

[100] In November 2023, she acquired British fashion magazine i-D from Vice Media Group and became its chief executive officer.

[103] In March 2024, she and her husband Joshua Kushner revived Life magazine for print and digital distribution through Bedford Media in partnership with Dotdash Meredith.

[106] In April 2015, Kloss launched Kode with Klossy, an initiative for teaching girls about computer science, with support from Estée Lauder.

[107] She partnered with Flatiron School and Code.org to offer an annual scholarship for young girls interested in computer science and software engineering as part of the initiative.

[108] The same year, she also launched a free two-week summer coding camp for girls aged 13–18, also called Kode With Klossy.