Background: Psychological distress has become a significant public health concern, and gender differences in psychological distress are well documented in the literature. This study investigated determinants of gender disparities in psychological distress among youth and adults in South Africa. Methods: This study data used obtained from the 2017 National HIV Prevalence, Incidence, Behaviour, and Communication Survey conducted using a multi-stage stratified random cluster sampling design. Multivariate backward stepwise logistic regression models were used to determine the factors associated with psychological distress among males and females. Results: In the male model, the odds of psychological distress were significantly higher among those who reported fair/poor self-rated health [AOR=1.7% (95% CI: 1.2-2.4), p=0.003], and excessive alcohol users [AOR=1.6% (95% CI: 1.1-2.3), p=0.008]. The odds were significantly lower among those with tertiary education level [AOR=0.5% (95% CI: 0.3-0.9), p=0.031], those from rural formal/farm areas [AOR=0.6% (95% 0.4-1.0), p=0.046], and those who were HIV negative [AOR=0.7% (95% CI: 0.4-1.0), p=0.051]. In the female model, the odds of psychological distress were significantly higher among those who reported fair/poor self-rated health [AOR=2.6% (95% CI: 2.0-3.4), p<0.001], and excessive alcohol users [AOR=2.0% (95% CI: 1.3-3.1), p=0.002]. The odds were significantly lower among the employed [AOR=0.7% (95% CI: 0.5-0.9), p=0.002], those from rural informal/tribal areas [AOR=0.6% (95% CI: 0.5-0.8), p=0.001], rural formal/farm areas [AOR=0.6% (95% CI: 0.4-0.9), p=0.015], and those with correct HIV knowledge and myth rejection [AOR=0.6% (95% CI: 0.4-0.7), p<0.001]. Conclusion: The findings highlight the need for tailored gender-specific interventions and targeting identified high-risk groups. The finding also underscores the importance of integrated interventions to address the adverse effects of harmful alcohol use and HIV-positive serostatus on psychological distress.