Plasmodium falciparum is responsible for the majority of malaria cases and deaths worldwide. In malaria endemic areas, natural immunity to blood stage infection is acquired over several exposures to the parasite and is thought to rely on antibodies. Antibodies can protect from severe disease through different effector functions, with complement activation lately emerging as an important feature of protective humoral responses to malaria. Plasmodium parasites have however evolved several mechanisms to evade complement attack, including the recruitment of complement down-regulatory proteins like Factor H (FH) and C1 esterase inhibitor (C1-INH). In this study, we report that merozoite-specific antibodies acquired naturally after infection activate the complement cascade in an exposure-dependent manner. Using plasma samples from convalescent children and exposed adults collected respectively in Hohoe and Accra (Ghana), we show that the ability to fix C1q and activate the classical pathway is similar for antibodies deriving from the two donors groups. However, downstream complement activation shown as deposition of the membrane attack complex (MAC) is strikingly higher with antibodies from children compared to antibodies from adults. Moreover, we demonstrate that antibodies from naturally exposed children can interfere with the merozoite recruitment of FH, but not of C1-INH. With the aim of neutralizing parasite evasion of the complement classical pathway, we develop a murine monoclonal antibody targeting PfMSP3, the binding partner of C1-INH on the merozoite surface. We demonstrate that this antibody can effectively block the binding of C1-INH to the parasite surface, unlike the naturally acquired ones. Using cryogenic electron microscopy, we obtain a low-resolution structure of the monoclonal antibody in complex with PfMSP3, which is the first reported structural data for this antigen. We propose targeting parasite antigens binding to complement down-regulators, together with leading vaccine candidate antigens, as a novel strategy to enhance the efficacy of future malaria vaccines.