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Spring viraemia of carp virus (SVCV) is a viral fish pathogen causing high mortality in several carp species and other cultivated fish. However, robust anti-SVCV drugs currently are extremely scarce. For the purpose of seeking out anti-SVCV drugs, here a total of 35 arctigenin derivatives were designed, synthesized and evaluated for their anti-viral activities. By comparing the inhibitory concentration at half-maximal activity (IC50) of the 15 screened candidate drugs (max inhibitory response surpassing 90%) in epithelioma papulosum cyprini (EPC) cells infected with SVCV, 2Q and 6 A were chosen for additional validation studies, with an IC50 of 0.077 μg/mL and 0.095 μg/mL, respectively. Further experiments revealed that 2Q and 6 A could significantly decrease SVCV-induced apoptosis and have a protective effect on cell morphology at 48 and 72 h post-infection. Moreover, the reactive oxygen species (ROS) induced upon SVCV infection could be obviously inhibited by 2Q and 6 A, while SVCV-infected cells were clearly observed. On account of these findings, 2Q and 6 A could have a promising application for the treatment of infection of SVCV and provide a considerable reference for novel antivirals in aquaculture.A total of 35 arctigenin derivatives were synthesized and evaluated for their anti-SVCV activities.2Q and 6 A displayed a robust inhibitory effect on SVCV proliferation in EPC cells.Structure-activity relationship showed the importance of the length of the R3 substituted group.