Polyoxometalates are promising inorganic drugs with antiviral activity. However, they pose a risk to human because of their potential accumulation in the body. Polyoxometalates encapsulated with berberine from a traditional Chinese herb may exhibit lower cytotoxicity. In this study, the antiviral effects of four berberine-based organic–polyoxometalate hybrids (BR-POMs) on BHK-21 and PK-15 cells were evaluated in vitro using encephalomyocarditis virus (EMCV) or pseudorabies virus (PRV) models. The collected cells were used for quantitative polymerase chain reaction analysis. The supernatants were collected to quantify the viral loads using a tissue culture infectious dose (TCID₅₀) assay in vitro. EC₅₀ and CC₅₀ were determined through dose–response experiments, and the EC₅₀/CC₅₀ ratio was used as a selectivity index to measure the antiviral activity. The results demonstrate that all BR-POMs exhibited certain antiviral activity. The BR-POMs did not exert toxicity against the EMCV- or PRV-infected cells at the tested concentration (CC₅₀ > 40 μM). Notably, BR-EuSiW (EC₅₀ 15.07 μM, CC₅₀ 651.2 µM, SI 43.21) exerted antiviral effects by acting on the virus at its biosynthesis stage, thereby inhibiting virus proliferation in a dose-dependent manner. This study demonstrates that organic–polyoxometalate hybrids represent a new strategy for developing antivirals against EMCV.