The world is currently witnessing a rise in viral infections, while the availability of antiviral drugs remains limited. Traditional Chinese medicine (TCM) has historically served as a valuable source of novel compounds for disease treatment. In this study, we assessed the antiviral potential of various TCM compounds using Drosophila melanogaster as a model organism. Our findings reveal that natural polysaccharide extracts, prepared from 10 commonly used medicinal herbs or fungi, exhibit antiviral activity against two picorna-like viruses. Importantly, the antiviral effect is not directly attributable to the compound itself but is instead mediated by cellular responses induced by treatment with the extract. We observed that the polysaccharide extract triggers a broad transcriptional response, which partially overlaps with NF-κB pathway activation in Drosophila. However, the antiviral activity of the extract was independent of classical innate immune pathways, such as RNA interference or NF-κB signaling. Instead, the extract appears to uniquely stimulate detoxification pathways, including upregulation of cytochrome P450 and glutathione S-transferase genes, which correlates with its antiviral effects.