Zoonotic and vector-borne infectious diseases are among the most direct human health consequences of biodiversity change. The COVID-19 pandemic increased health policymakers' attention on the links between ecological degradation and disease, and sparked discussions around nature-based interventions to mitigate zoonotic emergence and epidemics. Yet, although disease ecology provides an increasingly granular knowledge of wildlife disease in changing ecosystems, we still have a poor understanding of the net consequences for human disease. Here, we argue that a renewed focus on wildlife-borne diseases as complex socio-ecological systems-a paradigm-is needed to identify local interventions and transformative system-wide changes that could reduce human disease burden. We discuss longstanding scientific narratives of human involvement in zoonotic disease systems, which have largely framed people as ecological disruptors, and discuss three emerging research areas that provide wider system perspectives: how anthropogenic ecosystems construct new niches for infectious disease, feedbacks between disease, biodiversity and social vulnerability and the role of human-to-animal pathogen transmission ('spillback') in zoonotic disease systems. We conclude by discussing new opportunities to better understand the predictability of human disease outcomes from biodiversity change and to integrate ecological drivers of disease into health intervention design and evaluation.This article is part of the discussion meeting issue 'Bending the curve towards nature recovery: building on Georgina Mace's legacy for a biodiverse future'.