This study explores the antiviral potential of Graptopetalum paraguayense (GP) against SARS-CoV-2 nonstructural proteins (NSPs). GP, a plant known for its health benefits, has previously shown strong antiviral activity against HSV-1, and although the two viruses have different taxonomy, its effectiveness against the new coronavirus was also examined. LC-ESI-QTOF-MS/MS analysis identified fourteen polyphenolic metabolites in GP, including procyanidins and flavonol glucosides, compounds associated with anti-coronavirus properties. These compounds were tested using molecular docking and ONIOM(B3LYP/6-31+G(d,p):UFF) quantum chemical calculations to assess their binding affinity to eight SARS-CoV-2 NSPs critical for viral replication and transcription. The results revealed that GP compounds, such as procyanidin B2, kaempferol-3-O-glucoside, and epicatechin-3-O-galactoside, had strong binding affinities to NSP14, NSP5, and NSP15, respectively, suggesting their potential to inhibit viral replication. Compared to known NSP inhibitors from the RCSB Protein Data Bank, GP-derived compounds demonstrated comparable or superior interaction energies in several cases. This investigation highlights GP's therapeutic potential as a natural antiviral against SARS-CoV-2. The findings provide new insights into the role of plant-derived polyphenols in targeting viral proteins and contribute to further experimental and clinical studies to validate these compounds as candidates for anti-coronavirus therapies.