B-cell activating factor (BAFF) plays a key role in the normal regulation of B cell development and immune response. Its abnormal expression level is accompanied by the occurrence of various autoimmune diseases. Therefore, BAFF is an effective target for the treatment of such diseases. Here, we report a new anti-BAFF monoclonal antibody. Based on improved in vitro immunization method, we used a recombinant BAFF containing unnatural amino acid p-nitro-phenylalanine (pNO₂Phe) as an antigen to trigger immune response in vitro. The plasma cells were sorted by flow cytometry (FACS), and the antibody library was constructed based on the sorted plasma cells. The high affinity antigen-binding fragments were panned by phage display technology, and finally the anti-BAFF human IgG was obtained. The antibody demonstrated its ability to neutralize BAFF effectively both in vitro and in vivo. We propose that this novel full-length human anti-BAFF monoclonal antibody is a promising therapeutic candidate for the treatment of autoimmune diseases.