Linking climatic factors, ecosystem properties, biodiversity and ecosystem services (ESS) is critical for projecting future impacts of climate change on ESS. However, it is difficult to quantitatively link these components, in particular at large scales. Here we develop a new, comprehensive framework, incorporating direct and indirect effects of biodiversity and climate, as well as of socio-economic drivers and ecosystem disservices (human diseases) on cultural ESS. We applied our framework to wildlife tourism in Africa and collected climate, ecosystem, large mammal, socio-economic, malaria and tourist data from 64 savannah national parks across 10 countries in eastern and southern Africa. We used Structural Equation Modeling (SEM) to quantitatively test the direct and indirect relationships proposed in our framework between these multiple factors and wildlife tourism. We found significant relationships between climatic factors, large mammal densities and tourist numbers that were also influenced by travel cost, park quality (e.g. road quality, accommodation) and park management, but not by malaria. We found in particular a positive association between biodiversity and wildlife tourism, i.e. tourist numbers increased with large predator densities. We also detected a direct relationship between annual temperature and wildlife tourism. Furthermore, we found an indirect, but weak association between other climatic factors and wildlife tourists mediated via large mammal densities. We conclude that multiple factors influenced wildlife tourism across large spatial scales and a particularly important factor was biodiversity (i.e. charismatic large mammals). The direct and indirect links between climate, large mammals and wildlife tourism imply negative consequences of climate change, in particular of increasing temperatures for biodiversity and ESS provisioning in African savannahs. Our study demonstrates that a comprehensive quantitative understanding of direct and indirect relationships between climate, biodiversity, socio-economic drivers and ESS increases the value and applicability of ESS concepts for decision-making in politics and society.