The 2015 El Niño-triggered drought in Southern Africa caused widespread economic and livelihood disruption in South Africa, imposing multiple physical and health challenges for rural populations including people living with HIV (PLHIV). We examined the economic, social and demographic impacts of drought drawing on 27 in-depth interviews in two cohorts of PLHIV in Hlabisa, uMkhanyakude district, KwaZulu-Natal. Thematic analysis revealed how drought-enforced soil water depletion, dried-up rivers, and dams culminated in a continuum of events such as loss of livestock, reduced agricultural production, and insufficient access to water and food which was understood to indirectly have a negative impact on HIV treatment adherence. This was mediated through disruptions in incomes, livelihoods and food systems, increased risk to general health, forced mobility and exacerbation of contextual vulnerabilities linked to poverty and unemployment. The systems approach, drawn from interview themes, hypothesises the complex pathways of plausible networks of impacts from drought through varying socioeconomic factors, exacerbating longstanding contextual precarity, and ultimately challenging HIV care utilisation. Understanding the multidimensional relationships between climate change, especially drought, and poor HIV care outcomes through the prism of contextual vulnerabilities is vital for shaping policy interventions.