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As one of the most serious pathogens in the freshwater aquatic environment, spring viraemia of carp virus (SVCV) induces a high mortality rate in several cyprinid fishes. In this study, we designed and synthesized a total of 44 coumarin derivatives to evaluate the anti-SVCV activity. By comparing the inhibitory concentration at half-maximal activity (IC50), two imidazole coumarins (B4 and C2) were selected, with maximum inhibitory rates on SVCV more than 90%. Mechanistically, B4 or C2 did not affect viral adhesion and delivery from endosomes to the cytosol. Further, B4 and C2 could decline the apoptosis in SVCV-infected cells and the viral activated caspase-3, 8, 9 activities. Other results showed that SVCV induced the cytoskeletal structure to be a circumferential ring of microtubules near the nucleus, with occurring a disrupted microfilament organization. In comparison, cytoskeleton structure in drug-treated cells kept complete. In addition, the cellular microstructure in drug treatments showed no significant change; while SVCV-infected cells were seriously shrunk, and observed typical apoptotic features including cell shrinkage, volume reduction and cell blebbing. More importantly, B4 and C2 enhanced anti-oxidative enzyme gene expression and triggered the Nrf-2 pathway to keep balance of intracellular redox state. Therefore, the use of two imidazole coumarins (B4 and C2) could be a viable way of preventing and controlling SVCV infection.Two imidazole coumarins inhibit SVCV replication in host cells by activating the Nrf-2 pathway to keep balance of intracellular redox state, and they could be a potential viable way of preventing and controlling SVCV infection.A total of 44 coumarins were synthesized for evaluation on their anti-SVCV activity.Two imidazole coumarins have a maximum inhibitory effect on SVCV more than 90%.SVCV could destroy the cytoskeletal structure and cellular microstructure of fish cells.SVCV may induce EPC cell apoptosis mainly through the mitochondrial signal.