The study reviewed the applications of the water–energy–food (WEF) nexus for knowledge generation and decision-making in the Global South. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol identified 336 studies from the Web of Science and Scopus datasets. One hundred eighty-five articles applied WEF nexus tools to improve the understanding of WEF nexus interactions and to show the potential of nexus applications. The other articles (151) focused on nexus applications to guide planning and decision support for resource allocation and policy formulation. Environment, climate, ecosystems, land, and socio-economics were other popular nexus dimensions, while waste and economy were considered to a lesser extent. Limitations associated with nexus applications included unavailability of data, uncertainties from data sources, scale mismatch and bias. The inability of nexus tools to capture the complex realities of WEF interactions is hindering adoption, especially for policy formulations and investment planning. Data limitations could be solved using a sound scientific basis to correct uncertainties and substitute unavailable data. Data gaps can be bridged by engaging stakeholders, who can provide local and indigenous knowledge. Despite the limitations, applying nexus tools could be useful in guiding resource management. Limitations associated with nexus applications included – investment planning. Plausible pathways for operationalising the WEF nexus are discussed.