BACKGROUND: As infectious diseases approach global elimination targets, spatial targeting is increasingly important to identify community hotspots of transmission and effectively target interventions. We aimed to synthesise relevant evidence to define best practice approaches and identify policy and research gaps. OBJECTIVE: To systematically appraise evidence for the effectiveness of spatially targeted community public health interventions for HIV, tuberculosis (TB), leprosy and malaria. DESIGN: Systematic review. DATA SOURCES: We searched Medline, Embase, Global Health, Web of Science and Cochrane Database of Systematic Reviews between 1 January 1993 and 22 March 2021. STUDY SELECTION: The studies had to include HIV or TB or leprosy or malaria and spatial hotspot definition, and community interventions. DATA EXTRACTION AND SYNTHESIS: A data extraction tool was used. For each study, we summarised approaches to identifying hotpots, intervention design and effectiveness of the intervention. RESULTS: Ten studies, including one cluster randomised trial and nine with alternative designs (before-after, comparator area), satisfied our inclusion criteria. Spatially targeted interventions for HIV (one USA study), TB (three USA) and leprosy (two Brazil, one Federated States of Micronesia) each used household location and disease density to define hotspots followed by community-based screening. Malaria studies (one each from India, Indonesia and Kenya) used household location and disease density for hotspot identification followed by complex interventions typically combining community screening, larviciding of stagnant water bodies, indoor residual spraying and mass drug administration. Evidence of effect was mixed. CONCLUSIONS: Studies investigating spatially targeted interventions were few in number, and mostly underpowered or otherwise limited methodologically, affecting interpretation of intervention impact. Applying advanced epidemiological methodologies supporting more robust hotspot identification and larger or more intensive interventions would strengthen the evidence-base for this increasingly important approach. PROSPERO REGISTRATION NUMBER: CRD42019130133.