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BACKGROUND: This study aimed to evaluate the association between asymptomatic Plasmodium falciparum infection and poor intellectual development in primary school children in the Volta Region of Ghana.METHODS: This was a cross-sectional study conducted among children from 5 primary schools in 3 districts in the Volta region of Ghana. Questionnaires were administered, and blood samples collected for malaria investigation using Rapid diagnostic test (RDT) and microscopy. School performance was used to assess intellectual development in the children. Arithmetic was the subject of choice for the standardized test. Pearson chi square test was used to evaluate the association between Plasmodium falciparum and poor school performance. Multivariate analysis was used to identify factors independently associated with risk of poor school performance.RESULTS: Out of 550 children, 305(55.45%) tested positive for malaria with RDT and 249(45.27%) positive with microscopy. Children from the Evangelical Presbyterian (EP) primary school in Afegame had the highest prevalence of Plasmodium falciparum infection with both RDT (92, 74.80%) and microscopy (73, 59.35%). Two hundred and fifteen students (39.09%) failed the arithmetic school test. EP primary school in Afegame recorded the highest frequency of poor school performance among the children (53.66%). School performance was significantly associated with RDT malaria diagnosis with failure rate higher among children who were RDT positive (135, 62.79%, p=0.005). Lower mean scores were seen in children with positive RDT result (47.35, [SD 30.85], p=0.021). Plasmodium falciparum infection (RDT) was independently associated with increased risk of poor school performance (AOR, 1.92, p=0.003).CONCLUSION: An urgent scale-up of malaria control program targeting school-going children in this region is needed to mitigate the possible negative impact of Plasmodium falciparum infection on their intellectual development.