Here, we report the design, synthesis, structure-activity relationship studies, antiviral activity, enzyme inhibition, and druggability evaluation of dihydrofuro[3,4-<i>d</i>]pyrimidine derivatives as a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Compounds <b>14b</b> (EC<sub>50</sub> = 5.79-28.3 nM) and <b>16c</b> (EC<sub>50</sub> = 2.85-18.0 nM) exhibited superior potency against a panel of HIV-1-resistant strains. Especially, for the changeling mutations F227L/V106A and K103N/Y181C, both compounds exhibited remarkably improved activity compared to those of etravirine and rilpivirine. Moreover, <b>14b</b> and <b>16c</b> showed moderate RT enzyme inhibition (IC<sub>50</sub> = 0.14-0.15 μM), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, <b>14b</b> and <b>16c</b> exhibited favorable pharmacokinetic and safety properties, making them excellent leads for further development.