Nature-based solutions (NbS) —i.e. working with and enhancing nature to address societal challenges— feature with increasing prominence in responses to climate change, including in the adaptation plans of the most vulnerable nations. Although evidence for the effectiveness of NbS for adaptation is growing, there is less evidence on whether and how NbS reduce vulnerability to climate change in the Global South, despite this region being home to most of the world’s most climate-vulnerable people. To address this, we analysed the vulnerability-reduction outcomes of 85 nature-based interventions in rural areas across the Global South, and factors mediating their effectiveness, based on a systematic map of peer-reviewed studies encompassing a wide diversity of ecosystems, climate impacts, intervention types and institutions. We applied an analytical framework based on social-ecological systems and climate change vulnerability, coding studies with respect to six pathways of vulnerability reduction: social and ecological exposure, sensitivity, and adaptive capacity. We find widespread effectiveness of NbS in the dataset with 95% providing positive outcomes for climate change adaptation. Overall, nature-based interventions reduced vulnerability primarily by lowering ecosystem sensitivity to climate impacts (73% of interventions), followed by reducing social sensitivity (43%), reducing ecological exposure (37%), and/or increasing social adaptive capacity (34%), ecological adaptive capacity (18%) and reducing social exposure (12%). With an analysis of mediating factors, we show that vulnerability-reduction effectiveness was affected as much by social and political factors as by technical considerations. Indeed configurations of existing and introduced formal and informal institutions appear central to the efficacy and distributive effects of the studied interventions. We conclude that attention to the distinct pathways through which vulnerability is reduced can help maximise the benefits of NbS and that to be successful, careful consideration is required on their applicability to particular circumstances as well as their social dimensions.