Abstract: To identify highly effective antiviral compounds and develop green antiviral agents for plants, 21 α-hydroxy-γ-butyrolactone derivatives were designed and synthesized. Their structures were characterized using ¹H NMR, ¹³C NMR and HRMS. The in vivo antiviral activities against tobacco mosaic virus (TMV) were evaluated in three modes (inactivation, curative, and protective). Bioassay results revealed that many of the target compounds exhibited potent anti-TMV activities. Notably, compound 8o displayed prominent inactivation activity with an EC₅₀ value of 226.2 μg/mL, which was significantly superior to ribavirin (EC₅₀ = 308.4 μg/mL).