This study aimed to understand how social determinants—the economic and social factors that affect health and well-being—are associated with self-reported and biological alcohol and other drug misuse in South Africa among women living with HIV. Logistic regression analyses were performed using baseline data from an implementation science trial conducted from 2015 to 2018 with 480 Black and Coloured women who were living with HIV and reported recent alcohol or other drug misuse. Educational attainment, type of housing, access to running water, food insecurity, and housing instability were examined. Women with higher education had reduced odds of any drug misuse—both biological (aOR: 0.53; 95% CI: 0.33–0.84) and self-reported (aOR: 0.37; 95% CI: 0.22–0.64). Women living in formal housing had increased odds of a positive alcohol screening test (aOR: 1.92; 95% CI: 1.16–3.18) and women with housing instability had increased odds of self-reported alcohol misuse—daily (aOR: 1.99; 95% CI: 1.18–3.35) and weekly (aOR:1.91; 95% CI: 1.19–3.07). Food insecurity was associated with reduced odds of self-reported alcohol misuse (aOR: 0.40; 95% CI: 0.25–0.64) and increased odds of self-reported drug misuse (aOR: 2.05; 95% CI: 1.16–3.61). These findings indicate the complexity of the relationship between social determinants and alcohol and other drug misuse, and may have implications for addressing social and structural determinants as part of multilevel interventions focused on reducing alcohol and other drug misuse among key populations of women in South Africa.