SARS-CoV-2 exoribonuclease (ExoN) is essential for viral replication, contributing to proofreading, RNA synthesis, and genomic RNA recombination. As such, it represents a promising target for antiviral drugs. Several low-molecular-weight inhibitors, including disulfiram and aurintricarboxylic acid (ATA), have been reported to inhibit ExoN activity. Computational studies have also suggested that various natural phenolic compounds may inhibit ExoN; however, their inhibitory potency remains largely unknown. In this study, we systematically evaluated the inhibitory potency of 60 phenolic phytochemicals, including flavonoids, phenolic acids, coumarins, and other related compounds, using a dual-assay approach, with ATA as the reference inhibitor. Initially, we used nano-differential scanning fluorimetry to assess the thermal stabilization or destabilization of the enzyme induced by compound binding. Subsequently, we performed a TBE-PAGE-based enzymatic activity assay to examine ExoN activity inhibition. Selected compounds were then validated using a FRET-based enzymatic assay. While none of the compounds achieved the ATA’s inhibitory efficacy, three compounds demonstrated measurable inhibitory activity: myricetin (IC ₅₀ = 142 µM), ellagic acid (IC ₅₀ = 44.4 µM), and shikonin (IC ₅₀ = 7.92 µM). Our dual assay approach, complemented by crosslinking experiments, revealed that shikonin exhibits a distinct inhibitory mechanism, possibly involving the disruption of ExoN subunit interactions. These findings emphasize the necessity of experimental validation following in silico screening, particularly for promiscuous chemicals such as phenolic natural products. This approach may help to narrow down rationally designed compounds for further optimization.