Antibody-mediated rejection (ABMR) remains a significant challenge in renal transplantation and often leads to graft dysfunction and loss. In this report, we describe a case of rapid-onset ABMR in a recipient with a low immunological risk. Despite the absence of DSA in pre-transplant sera, post-transplant monitoring revealed significant HLA-Bw4-mediated immune activation. A 48-year-old female with end-stage renal disease and a prior history of pregnancy underwent deceased-donor renal transplantation. Pre-transplant, the patient reacted weakly only to B51 and no preexisting DSAs were detected. The patient received anti-thymocyte globulin (ATG) and methylprednisolone for the induction of immunosuppression and was maintained on a standard immunosuppressive regimen of tacrolimus, mycophenolate, and prednisone. After transplantation, the patient’s serum creatinine started to rise on postoperative day (POD) 8, prompting a graft kidney biopsy on POD 9. The biopsy revealed mild interstitial infiltration of mononuclear cells and intraglomerular leukocytic influx, while immunofluorescence staining revealed diffuse C4d staining along the peritubular capillaries. Single-antigen identification test showed that the B51 beads, which were weakly positive before transplantation, exhibited strongly positive anti-HLA-Bw4 antibodies. Based on the graft biopsy findings and single-antigen bead analysis, ABMR due to HLA-B51-mediated allosensitization to HLA-Bw4 was identified. Although we were unable to investigate the HLA typing of the patient’s spouse, HLA alloimmunization may have occurred as a consequence of her previous pregnancy. The patient underwent six sessions of plasmapheresis, intravenous immunoglobulin, and rituximab, and after the course of anti-rejection treatments, the patient's renal function has been well maintained to this date. This clinical case demonstrated the rapid development of ABMR within 8 days of post-transplantation due to HLA-Bw4. Although antibodies against public epitopes are not generally regarded as risk factors for ABMR, they may act as possible contributors. Thus, comprehensive immunological monitoring and early therapeutic intervention may be crucial for optimizing graft outcomes.