The synthesis of original imidazo[1,2-a]pyridines bearing a phenethylthiomethyl side chain at the 3 position and a (hetero)aryl substituent on the 6 or 8 position, and their antiviral activities are reported. From the synthesized compounds, the 6-halogeno and 6-phenylimidazo[1,2-a]pyridine derivatives 4c-d and 5b were the most potent against human cytomegalovirus (CMV) and/or varicella-zoster virus (VZV), whereas several other congeners (i.e., 5e, 5g, 5i, 5l, 5n, 5p, 5q, and 5t), while less potent, were equally or more selective in their inhibitory activity against both VZV and CMV. These compounds showed similar activity against thymidine kinase competent (TK(+)) and deficient (TK(-)) VZV strains, demonstrating a mechanism of action independent of the viral thymidine kinase.