Mntambo was born and raised in South Africa during apartheid, an experience that has significantly shaped her practice. After briefly studying forensic psychology in college, Mntambo transferred to the Michaelis School of Fine Art in Cape Town, where she began experimenting with cowhide. She was trained under a taxidermist who taught her the labor-intensive process of stretching and molding cowhide into a final form. As Mntambo observes, cows have had centuries-long cultural resonance with civilizations across the globe, thereby connecting her work to audiences broadly. In addition to working with cowhide, Mntambo has also developed a bronze sculpture practice. The artist casts her body to make monumental figurative works that feature her with animal elements, such as horns and fur, that allude to mythological and feminist themes. Mntambo has also worked in performance, video, and photography, all of which continue her exploration of the symbiotic relationship between humans and animals.

Mntambo earned an MFA from the Michaelis School of Fine Art in 2007. She has participated in exhibitions at the Zeitz MoCAA in Cape Town; the Museum of Fine Arts, Boston; and the Brooklyn Museum, among others. Mntambo was also featured in the Venice Biennale in 2015 and the Dakar Biennale in 2008, 2010, and 2016. She was a Civitella Fellow in 2013, and she won the AGO Photography Prize in 2014. Her work first entered the Studio Museum permanent collection in 2018.