Piglets afflicted with Porcine Epidemic Diarrhea Virus (PEDV) experience severe diarrhea and elevated death rates, leading to substantial financial losses in the pig farming sector. The objective of this study is to investigate the impact of polyphenols on PEDV within Vero cells by utilizing different methodologies to evaluate their anti-PEDV effect. By producing 30 polyphenols, we have discovered that No.2, No.5, No.7 and No.17 exhibit properties that make them effective against PEDV, serving as potential drugs. The findings showed that in a clear dose-dependent manner, the mRNA levels of PEDV were significantly inhibited in the high, middle, and low-dose groups of No.2, No.5, No.7 and No.17, when compared to the PEDV control. The four tested polyphenols significantly inhibited the levels of PEDV N contents and viral titers. Furthermore, concentration of cytotoxicity 50% (CC