EMCV is a significant zoonotic pathogen that causes severe encephalitis and myocarditis, particularly in pigs, posing substantial economic and public health challenges. Nuclear dot protein (NDP) 52 is an important autophagy adaptor protein known to target microbial pathogens, including viruses into autophagosomes to facilitate the selective autophagy process. Here, we investigated the interaction between EMCV and NDP52. We found that NDP52 negatively regulates the entry and replication phases of EMCV and interacts with EMCV VP1/VP2 proteins to mediate its autophagic degradation. Moreover, we show that EMCV 2C protein interacts with NDP52 through its N-terminal region to trigger the autophagic degradation of NDP52 via the involvement of the late endosomal molecules, Rab7 and Rab9. Our study reveals a novel mechanism by which EMCV uses its non-structural protein 2C to hijack the autophagy pathway, evading host antiviral responses and promoting survival.