The monoclonal antibody CIS43 preferentially binds the junctional region of circumsporozoite protein (PfCSP) and is highly protective in humans. Here, we develop an pipeline to improve antigen-antibody interaction energies and apply it to CIS43 variants elicited in CIS43-germline knock-in mice. Improved binding of CIS43 variants to the CIS43 junctional epitope (PfCSP peptide 21) was achieved by introducing single and double amino acid substitutions in the peptide 21-proximal heavy- and light-chain-variable regions. The best designed variant, antibody P3-43-LS, was 2- to 3-fold more protective than antibody CIS43-LS, the clinical version of CIS43 with half-life extending leucine-serine (LS) mutations, and had comparable protection to the current best-in-class antibody (iGL-CIS43.D3-LS) to this region. Crystal structures of the improved antibodies revealed atomic-level interactions accounting for gains in binding affinity. This approach to improve antibody affinity can thus be used to enhance potency of PfCSP monoclonal antibodies.