People can develop immunity to malaria, hence the global search for a vaccine. However, it is still unclear how immunity is acquired, and few studies have investigated functional antibody assays in relation to clinical outcomes. We have developed a functional assay to measure antibody-mediated phagocytosis of merozoites, and have applied this to a longitudinal cohort study conducted in a malaria endemic region of Papua New Guinea (PNG). Opsonising antibody responses to merozoites were found to: i) increase with age, ii) be enhanced by concurrent infection, and iii) correlate with protection from clinical episodes and high-density parasitemia. Stronger protective associations were observed in individuals with no detectable parasitemia at baseline. This study presents the first evidence for merozoite phagocytosis as a correlate of acquired immunity and clinical protection against P. falciparum malaria.