Natural products have been a valuable source of efficient and low-risk pesticides. In this work, a series of novel sesamolin derivatives A0-A31 and B0-B4 were designed and synthesized via structural simplification of furofuran lignan phrymarolin II, and their antiviral and antibacterial activities were systematically evaluated. The bioassay results showed that compound A24 displayed remarkable inactivation activity against tobacco mosaic virus (TMV) with an EC 50 value of 130.4 μg/mL, which was superior to that of commercial ningnanmycin (EC 50 = 202.0 μg/mL). The antiviral mode of action assays suggested that compound A24 may obstruct self-assembly by binding to TMV coat protein (CP), thus resisting the TMV infection. In addition, compound A25 possessed prominent antibacterial activities, especially against Ralstonia solanacearum with an EC 50 value of 43.8 μg/mL, which is better than those of commercial bismerthiazol and thiodiazole copper . This research lays a solid foundation for the utilization of furofuran lignans in crop protection.