Reverse transcriptase (RT) is one of three key proteins responsible for the replication cycle of HIV-1 in the host. Several classes of inhibitors have been developed to target the enzyme, with non-nucleoside reverse transcriptase inhibitors forming first-line treatment. Previously, covalent RT inhibitors have been identified and found to bind irreversibly to commonly mutated residues such as Y181C. In this work we aim to circumvent the issue of NNRTI resistance through targeting K102, which has not yet been identified to confer drug resistance. As reported here, 34 compounds were synthesized and characterized biochemically and structurally with wild-type (WT) HIV-1 RT. Two of these inhibitors demonstrate covalent inhibition as evidenced by protein crystallography, enzyme kinetics, mass spectrometry, and antiviral potency in HIV-1 infected human T-cell assays. Display omitted •Computational/structure-guided design yielded potent noncovalent and covalent inhibitors.•Potent antiviral efficacy against HIV in cell culture was achieved by these NNRTIs.•A series of scaffolds and warheads for NNRTIs were used to covalently target K102.•Covalency for targeting K102 was demonstrated by structural and ESI MS TOF analysis.•One covalent inhibitor had 500 pM antiviral efficacy and therapeutic index of 9000.