Two isosteric series of 1,2,4-triazole and 1,3,4-thiadiazole derivatives were designed and synthesized in this work to be evaluated for their antiviral activity. Compounds 2-9 and 11-19 were synthesized and their antiviral activity was tested against herpes simplex virus type 1, HSV-1, using acyclovir, ACV, as a reference drug. In addition, molecular docking into the active site of HSV-1 thymidine kinase was performed to interpret the data obtained from biological testing, and all compounds were subjected to an in silico screening of their physicochemical properties to estimate their drug-likeness and safety. The results revealed that compound 7 was able to reduce the viral plaques by 50% at a dose of 80 μM, but interestingly, retained high selectivity compared to ACV (> 200 μM vs. 80 μM). The best effective and safe compound in this study, 7, was further tested for its combined effects with ACV on the anti-HSV-1 activity in the plaque reduction assay. Compound 7 proved to improve the selectivity of ACV and reduce its effective dose that produced 100% inhibition of viral plaques. The triazolopyrimidine 7 is suggested to be a promising candidate for further development as an antiherpetic agent. Molecular docking into the active site of HSV-1 thymidine kinase emphasized the superior interaction of compound 7.