Vaccines are urgently needed to reduce the burden of malaria and enable progress towards malaria elimination. However, the most advanced malaria vaccines have only achieved low to moderate protective efficacy in clinical trials in endemic populations. The sporozoite form of malaria is inoculated into the skin during an infected mosquito bite and targeting sporozoites by vaccines is an attractive strategy to prevent infection and subsequent clinical illness. We have established that following inoculation, sporozoites can be opsonized by antibodies and cleared by peripheral blood leukocytes, especially neutrophils, with additional roles for monocytes and natural killer cells. We identified the activating low affinity Fcγ receptors (FcγR), including FcγRIIa and FcγRIIIa/b, as critical for this activity. Using an in vivo passive immunization-challenge model, we confirmed that the Fc region is required for maximum efficacy of antibodies against sporozoites. In naturally-exposed populations in Africa, we found that these functional antibodies are only slowly acquired after repeated exposure, and effective antibodies are present among some adults. Further investigation of this mechanism in malaria vaccine trials confirmed its correlation with protection. In addition, we established that the circumsporozoite protein (CSP) is the major target of antibodies that promote opsonic phagocytosis and defined the activity of antibodies to different regions of CSP. We identified epitopes within the N-terminal region of CSP that are targeted by functional antibodies, and these epitopes are not included in current malaria vaccines. Our data highlight the importance of FcγR-mediated opsonic phagocytosis in immunity against sporozoites, and specific regions of CSP, and reveal potential new strategies for developing a highly effective vaccine against sporozoites.