1,4-Pentadien-3-one derivatives derived from curcumin possess excellent inhibitory activity against plant viruses. On the basis of this finding, a series of novel 1,4-pentadien-3-one derivatives containing a 1,3,4-thiadiazole moiety were designed and synthesized, and their structures confirmed by IR, ¹H-NMR, and C-NMR spectroscopy and elemental analysis. The antiviral activities of the title compounds were evaluated against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) in vivo. The assay results showed that most of compounds had remarkable antiviral activities against TMV and CMV, among which compounds , , , , , and exhibited good curative, protection, and inactivation activity against TMV. Compounds , , , , , and exhibited excellent protection activity against TMV, with EC values of 105.01, 254.77, 135.38, 297.40, 248.18, and 129.87 μg/mL, respectively, which were superior to that of ribavirin (457.25 µg/mL). In addition, preliminary SARs indicated that small electron-withdrawing groups on the aromatic ring were favorable for anti-TMV activity. This finding suggests that 1,4-pentadien-3-one derivatives containing a 1,3,4-thiadiazole moiety may be considered as potential lead structures for discovering new antiviral agents.