Background <p>Problematic substance use is associated with poor HIV clinical outcomes, including among adolescents and young adults (AYAs) living with HIV. Higher levels of potentially problematic substance use among those diagnosed with HIV during the COVID-19 pandemic may have been mediated by declining levels of social capital and varied depending on an individual’s level of anticipated stigma. We sought to determine whether social capital mediates the relationship between time of HIV diagnosis (pre- versus intra-pandemic) and potentially problematic substance use as a function of anticipated stigma.</p> Method <p>This moderated mediation analysis utilized baseline data from two demographically similar cohorts of young South Africans ages 18–24&#xa0;years who tested positive for HIV either before or during the COVID-19 pandemic. The relationships between time of diagnosis in relation to the COVID-19 pandemic, social capital, potentially problematic substance use, and anticipated stigma were analyzed using a series of logistic regression, mediation, and moderated mediation analyses.</p> Results <p>Compared to their peers diagnosed before the pandemic, young people diagnosed during the COVID-19 pandemic were more likely to screen positive for potentially problematic substance use (OR 3.561; CI 1.827, 6.943; <i>p</i> &lt; 0.001). Social capital was an inconsistent mediator of the relationship between time of diagnosis and potentially problematic substance use, such that lower social support observed among those diagnosed during the COVID-19 pandemic partially suppressed the positive association between pandemic time of diagnosis and potentially problematic substance use (indirect effect =  −0.363; CI −0.717, −0.119). There was a significant moderated mediation effect of anticipated stigma (index of moderated mediation = 0.028; CI 0.03, 0.061), indicating that the negative indirect effect of time of diagnosis on potentially problematic substance use weakened at higher levels of anticipated stigma.</p> Conclusion <p>Diagnosis during the COVID-19 pandemic was associated with a greater likelihood of screening positive for potentially problematic substance use. Although those diagnosed during the pandemic reported lower social capital, social capital was itself associated with potentially problematic substance use. However, this association weakened at high levels of anticipated stigma. These findings may suggest that diagnosis during the pandemic may have exposed those with higher social capital to social networks and norms conducive to substance use, underscoring the need for longitudinal research and interventions addressing the social contexts shaping substance use in this population.</p> Trial Registration <p>Some data from this study emanate from a pilot randomized controlled trial, which was prospectively&#xa0;registered at ClinicalTrials.gov (Identifier: NCT04568460) prior to participant enrollment.</p>