Abstract: To investigate how GCRV-encoded proteins interact with host cells and evade immune responses, this study focuses on the non-structural protein NS38 of type I GCRV. Using co-immunoprecipitation combined with mass spectrometry, we identified grass carp SAMHD1 as an interacting partner of NS38. Further co-IP and subcellular localization assays confirmed their interaction and co-localize in the cytoplasm, with the HD domain of SAMHD1 being the key region mediating the interaction with NS38. We also demonstrated that SAMHD1 inhibits GCRV replication. The overexpression of SAMHD1 in CIK cells significantly reduced viral copy numbers and alleviated cytopathic effects, whereas knockdown of SAMHD1 promoted viral replication. Notably, the antiviral effect of SAMHD1 was independent of interferon pathway activation and appeared to rely primarily on its dNTP triphosphohydrolase activity, which depletes intracellular dNTP pool and thereby restricts substrates for viral reverse transcription. Mechanistic studies revealed that GCRV NS38 induces SAMHD1 degradation via the autophagy-lysosome pathway, thereby counteracting its antiviral function. In summary, our study revealed that NS38 targets the host restriction factor SAMHD1 for degradation and facilitate the immune escape of GCRV. This finding enhances the understanding of GCRV pathogenesis and provides a potential target for the development of vaccines against GCRV.