His photographic work focuses heavily on the relationship between artist and subject, often exploring the nude in relation to the intimacy of studio photography.
[4] Fragmentation is a major feature of his work; he often depicts his subjects in fragments—torsos, arms, legs, or feet—rather than showing the entire body.
[7] He draws inspiration from the works of Robert Mapplethorpe and art historian and critic Brian O'Doherty.
As of 2024, Sepuya is Associate Professor in Media Arts and MFA program director at the University of California, San Diego.
[17][18] Four of his photographs are held in the collection of the Museum of Modern Art, New York, and he was included in its Spring 2018 exhibition New Photography.
[24][25] An art critic in The Nation wrote that Sepuya's photographs "almost too perfectly encapsulate the current tendency to see photography as a game of mirrors" and that his "conceptually self-questioning strategies and fastidious-almost-to-the-point-of-finicky aesthetics account, in part, for why he seems to be a must-have artist of the moment".