Plasmodium falciparum is a human-adapted apicomplexan parasite that causes the most dangerous form of malaria. P. falciparum cysteine-rich protective antigen (PfCyRPA) is an invasion complex protein essential for erythrocyte invasion. The precise role of PfCyRPA in this process has not been resolved. Here, we show that PfCyRPA is a lectin targeting glycans terminating with α2-6-linked N-acetylneuraminic acid (Neu5Ac). PfCyRPA has a >50-fold binding preference for human, α2-6-linked Neu5Ac over non-human, α2-6-linked N-glycolylneuraminic acid. PfCyRPA lectin sites were predicted by molecular modeling and validated by mutagenesis studies. Transgenic parasite lines expressing endogenous PfCyRPA with single amino acid exchange mutants indicated that the lectin activity of PfCyRPA has an important role in parasite invasion. Blocking PfCyRPA lectin activity with small molecules or with lectin-site-specific monoclonal antibodies can inhibit blood-stage parasite multiplication. Therefore, targeting PfCyRPA lectin activity with drugs, immunotherapy, or a vaccine-primed immune response is a promising strategy to prevent and treat malaria. Display omitted •Plasmodium falciparum CyRPA binds to carbohydrates with terminal 2-6-linked Neu5Ac•Lectin activity of Plasmodium falciparum CyRPA contributes to erythrocyte invasion•Targeting lectin activity with drugs and antibodies is a promising anti-malarial strategy Day et al. show that the essential Plasmodium falciparum invasion protein PfCyRPA is a lectin targeting 2-6-linked Neu5Ac. Molecular modeling, mutagenesis, and transgenic parasite studies show that PfCyRPA lectin activity is required for erythrocyte invasion. Drug and antibody inhibitors validate this activity as a therapeutic target to prevent and treat malaria.