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Helminth infections are consistently associated with reduced cardiovascular disease (CVD) risk, yet the biological mechanisms underlying this relationship remain unclear. The gut microbiome and metabolome are key regulators of cardiometabolic health and may mediate infection-associated effects on host physiology. Here we show that Schistosoma mansoni infection associates with distinct gut microbial and metabolic profiles linked to CVD risk in people living in Uganda. In a cross-sectional study of 209 individuals living in communities with contrasting S. mansoni endemicity, we profile the gut microbiome using 16S rRNA gene sequencing and the faecal metabolome using liquid chromatography-mass spectrometry. S. mansoni infection associates with increased gut microbial diversity and distinct taxonomic signatures, including enrichment of taxa such as Treponema and depletion of Prevotella and Streptococcus. Several infection-associated microbial taxa statistically mediate the relationships between S. mansoni infection and cardiovascular disease risk. Faecal metabolomic profiling identifies infection-associated metabolites, and integrative analyses showed linked microbe-metabolite networks associated with cardiovascular risk.These findings identify gut microbiome and metabolome signatures associated with S. mansoni infection and cardiovascular disease risk in Uganda. Although causality cannot be inferred, this work provides insight into host-parasite-microbiome interactions and highlights microbial and metabolic pathways relevant to cardiometabolic health.