To advance the development of highly efficacious vaccines, a greater understanding of the targets of protective immunity against P. falciparum malaria and the protective immune mechanisms is required. Naturally-acquired antibodies against merozoite antigens reduce parasitemia and protect against clinical disease, however a limited knowledge about key targets and protective effector mechanisms of antibodies have hampered blood-stage vaccine development. Recent studies established that acquired human antibodies to merozoites can activate the classical complement pathway, initiated by the fixation of C1q on the merozoite surface, which results in inhibition of erythrocyte invasion and merozoite lysis. Complement-fixing antibodies were strongly predictive of protection from clinical disease and high-density parasitemia. In order to identify key targets of complement fixing antibodies, we developed assays to quantify functional antibodies to multiple merozoite target antigens and evaluated antigen-specific responses in a longitudinal cohort of naturally exposed children in Papua New Guinea. While complement-fixing antibodies were generally found to increase with age and exposure, we found large variability in the complement-fixing activity antibodies to individual merozoite antigens, and we identified antigens that are prominent targets of complement-fixing antibodies. We identified several antigens for which complement-fixing antibodies were strongly associated with protection from symptomatic malaria, and our data suggests these antibodies protect by preventing high-density parasitemia. Further, we demonstrated that specific combinations of antigen-specific responses were associated with very high levels of protective immunity, approaching 95%. Interestingly, complement-fixing antibodies were much more strongly associated with protection from malaria than antibody activity quantified in growth-inhibition assays, which is the current functional assay used to evaluate blood-stage vaccines. This is the first study to quantify acquired functional antibodies to multiple antigens in an endemic population and identify functional antigen-specific antibodies and combinations linked with protective immunity. These findings identify new leads and approaches that could be investigated for vaccine development.