The rapid mutation rate of SARS-CoV-2 highlights the urgent need for continuous drug development to enhance both efficacy and safety. BPR2-D2, an angular coumarin derivative, has previously shown notable anti-influenza activity and broad-spectrum inhibitory effects against RNA viruses. In this study, we found that BPR2-D2 exhibits potent antiviral activity against multiple SARS-CoV-2 variants, including several variants of concern, at nanomolar concentrations. Notably, BPR2-D2 effectively disrupted viral RNA and protein synthesis in infected cells while mitigating pro-inflammatory cytokines triggered by viral replication. Our investigation of SARS-CoV-2 RdRp activity employed in silico analyses, including molecular docking, dynamic simulations, and binding free energy calculations. BPR2-D2 demonstrated superior binding affinity to the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 compared to remdesivir. Additionally, it exhibited an increased synergistic inhibitory activity against the viral enzyme when combined with remdesivir. Both cell-based and in vitro enzyme-based RdRp reporter assays validated BPR2-D2’s capacity to inhibit SARS-CoV-2 RdRp activity. The potential synergistic interaction between BPR2-D2 and remdesivir was investigated using cell-based combination assays. The results revealed a synergistic effect in reducing SARS-CoV-2 RNA synthesis, consistent with the in silico analysis. Collectively, these findings suggest that BPR2-D2, a repurposed small-molecule compound, effectively inhibits SARS-CoV-2 by modulating its RdRp function. This positions BPR2-D2 as a promising novel antiviral agent, while also providing insights into the complex molecular mechanisms underlying viral replication.