A new series of 4-substituted 3-methyl-1,5 diphenyl-1H-pyrazoles 4–11 has been synthesized and evaluated for its in vitro antiviral activity and cytotoxicity against herpes simplex virus type-1 grown on Vero African green monkey kidney cells through plaque-reduction assay method using acyclovir as a positive control. The synthesis was achieved through Claisen-Schmidt condensation reaction of 3-methyl-1,5-diphenyl-1H-pyrazole-4-carbaldehyde (3) with acetophenone derivatives to give various enones 4a–f which are considered an important synthon for the construction of different heterocyclic rings as isoxazoline, pyrazoline, pyrimidine, pyridine, and fused pyridine via several synthetic routes. Biological evaluation of the prepared compounds showed that 3-(4-methylphenyl)-5-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-4,5-dihydroisoxazole (5f), 6-(4-methylphenyl)-N-[(3-(methylsulfanyl)phenyl)]-4-(3 methyl-1,5-diphenyl-1H-pyrazol-4-yl)pyrimidin-2-amine (7), 6-(4-bromophenyl)-4-(3-methyl-1,5-diphenyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (8), and 2-amino-6-(4-bromophenyl)-4-(3-methyl-1,5-diphenyl-1Hpyrazol-4-yl) pyridine-3-carbonitrile (9) exhibited strong antiviral activity with IC50 (0.02, 0.04, 0.03, 0.03), respectively, compared to the used reference drug. The synthesized compounds were characterized by physical constants and the structures of the title compounds were confirmed by IR, 1 H NMR, mass spectra, and elemental analyses.