Malaria parasite invasion to host erythrocytes is mediated by multiple interactions between merozoite ligands and erythrocyte receptors that contribute toward the development of disease pathology. Here, we report a novel antigen prohibitin "PHB2" and identify its cognate partner "Hsp70A1A" in host erythrocyte that plays a crucial role in mediating host-parasite interaction during merozoite invasion. Using small interfering RNA (siRNA)- and glucosamine-6-phosphate riboswitch (glmS) ribozyme-mediated approach, we show that loss of Hsp70A1A in red blood cells (RBCs) or PHB2 in infected red blood cells (iRBCs), respectively, inhibit PHB2-Hsp70A1A interaction leading to invasion inhibition. Antibodies targeting PHB2 and monoclonal antibody therapeutics against Hsp70A1A efficiently block parasite invasion. Recombinant PHB2 binds to RBCs which is inhibited by anti-PHB2 antibody and monoclonal antibody against Hsp70A1A. The validation of PHB2 to serve as antigen is further supported by detection of anti-PHB2 antibody in patient sera. Overall, this study proposes PHB2 as vaccine candidate and highlights the use of monoclonal antibody therapeutics for future malaria treatment.