The role of risky sexual behaviour has been widely investigated across the sub-Saharan African HIV hyperendemic setting, with few studies having focused on the behaviour attributed to the deep-rooted, neurodevelopmentally-driven adverse childhood experiences (ACE) that sustain the endemic. We investigated the role of ACE on perinatal substance use outcomes in KwaZulu-Natal Province, South Africa, with 223 women being interviewed within one-week post-partum at a general hospital. Our secondary outcome was the occurrence of preterm birth delivery, which is understood to be linked to ACE. Study results suggest that the most common perinatal substance use was alcohol (n = 27, 12.11%), followed by tobacco (n = 18, 8.07%), with the prevalence of preterm birth delivery being 8.97% (n = 20, 8.97%). Regression analyses indicated increased ACE being significantly associated with perinatal alcohol (aOR = 1.45, 95% CI 1.22-1.72), tobacco use (aOR = 1.56, 95% CI 1.23-1.97) and preterm birth delivery (aOR = 1.21, 95% CI 1.03-1.43), independent of socio-economic status. When the model was further adjusted by HIV status, suppressed viral load was more significantly associated with lower odds of preterm birth delivery (aOR = 0.06, 95% CI: 0.01-0.24) than an unsuppressed status. Risk-behaviour reduction strategies should address the role of ACE on substance use and viral load, and hence possibly ART adherence, in HIV hyperendemic settings.