Climate change is directly and indirectly linked to human health, including through access to treatment and care. Our systematic review presents a systems understanding of the nexus between drought and antiretroviral therapy (ART) adherence in HIV-positive individuals in the African setting. Narrative synthesis of 111 studies retrieved from Web of Science, PubMed/MEDLINE, and PsycINFO suggests that livelihoods and economic conditions, comorbidities and ART regimens, human mobility, and psychobehavioural dispositions and support systems interact in complex ways in the drought-ART adherence nexus in Africa. Economic and livelihood-related challenges appear to impose the strongest impact on human interactions, actions, and systems that culminate in non-adherence. Indeed, the complex pathways identified by our systems approach emphasise the need for more integrated research approaches to understanding this phenomenon and developing interventions.