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A major natural killer (NK) cell and CD8⁺ T cell checkpoint is mediated by the inhibitory receptor NKG2A/CD94 and its ligand, human leukocyte antigen E (HLA-E) complexed with nine-amino acid HLA-Ia leader sequence-derived peptides termed VL9 (HLA-E-VL9). Here, we used structure-based design and high-throughput library screening to generate high-affinity antibodies that block NKG2A/CD94 interactions. These antibodies enabled direct NK and CD8⁺ T cell cytotoxicity and mediated NK cell antibody-dependent cellular cytotoxicity (ADCC). Anti-HLA-E-VL9 antibodies enhanced human NK cell line NK-92 killing of HLA-E-VL9⁺ human tumors in mice, demonstrating checkpoint inhibition activity in vivo. Moreover, HLA-E-VL9 was found to be expressed on primary human CD4⁺ T cells infected with HIV in vitro, and its engagement by HLA-E-VL9 antibodies drove elimination of infected cells by NK cell-mediated ADCC. HLA-E-VL9 antibodies also enhanced the killing of HIV-infected cells by NKG2A/CD94⁺ CD8⁺ T cells targeting an HIV Rev-derived epitope that complexes with HLA-E. Therefore, anti-HLA-E-VL9 antibodies represent a candidate therapeutic approach to eliminating pathogenic target cells by enhancing both NK cell and CD8⁺ T cell function and by promoting ADCC.