Responsive to desiccation 21 (RD21) is a papain-like cysteine protease (PLCP). PLCPs are involved in plant growth and development, as well as stress and plant immune responses. Currently, few studies have reported on the involvement of PLCPs in defence against viral infections. Here, we show that RD21 of strawberry (Fragaria vesca) interacts with the strawberry vein banding virus (SVBV) P6 protein. SVBV infection induces FvRD21 expression. Subcellular localization revealed that FvRD21 and P6 colocalize in the perinuclear and cytoplasmic regions. Further analysis showed that FvRD21 overexpression induces the autophagy pathway that degrades the P6 protein, destroys the function of P6 as a viral suppressor of RNA silencing (VSR), inhibits the pathogenicity of P6, and confers resistance to SVBV in strawberry plants. Moreover, mutant FvRD21 lost its ability to interact with SVBV P6 and did not affect P6 accumulation and VSR function. Additionally, abscisic acid (ABA) pretreatment of strawberry plants promoted FvRD21 upregulation and inhibited SVBV infection, and FvRD21 overexpression activated the ABA pathway. In summary, FvRD21 inhibits SVBV infection by degrading SVBV P6 through the autophagy pathway. Hence, this study provides a novel report on the defence strategy of strawberry plants against SVBV infections.