A series of novel 5-alkyl-6-Adamantylmethylpyrimidin-4(3H)-ones bearing various substituents at the C-2 position of the pyrimidinone ring were synthesized using a facile route and evaluated for their anti-HIV activity in MT-4 cells. The biological results demonstrated that the majority of the newly designed compounds possessed moderate efficiency in inhibiting the replication of the wild-type (WT) HIV-1 strain (IIIB) with EC50 values in the range from 0.10 to 5.39μm. Among them, 5b1 and 5b3 proved to be the two most active inhibitors against WT HIV-1 with EC50 values of 0.10 and 0.12μm, respectively, which were more active than nevirapine (NVP) in the same assay. In addition, HIV-1 reverse-transcriptase (RT) inhibition assay indicated that the representative compound 5b1 showed affinity to WT HIV-1 RT, and inhibited the activity of RT with an IC50 value superior to the reference drug NVP. Moreover, the preliminary structure–activity relationship (SAR) and the molecular modeling analysis of these new derivatives are also discussed.