<p>Oral submucous fibrosis (OSF) is a chronic, progressive, and potentially malignant disorder with limited therapeutic options. This study explored the therapeutic potential of <i>Solanum trilobatum</i> (<i>S.trilobatum</i>) using a network pharmacology and molecular docking approach. 5 phytochemicals from <i>S. trilobatum</i> were identified with favorable drug-likeness, good gastrointestinal absorption, and low predicted toxicity. Target analysis for 5 phytochemicals revealed 24 potential targets associated with OSF. The 24 targets were enriched in various pathways, and PPI analysis of the targets using MCODE identified six hub genes, namely PLG, ABCB1, PTGS2, HMGCR, NOS2, and MAPK3. Druggability analysis further confirmed that the identified hub genes could serve as potential therapeutic targets. ProteomicsDB analysis revealed the expression of the hub genes in the oral cavity. Docking confirmed that Solasodine exhibited significant binding affinities with the six targets, comparable to or stronger than the control drug dexamethasone, thereby suggesting their multitargeting potential. Molecular dynamics (MD) simulation (100 ns) was performed for Solasodine, as it exhibited the highest binding affinity across all six targets, and the simulation confirmed the formation of a stable ligand–protein complex. The bioactivity analysis further confirmed the therapeutic potential of the phytochemicals. This study provides preliminary evidence that <i>S. trilobatum</i> phytochemicals may function as multitarget modulators in OSF through the regulation of key genes. In vitro assays demonstrated that <i>S. trilobatum</i> leaf extract exhibited dose-dependent antioxidant (DPPH and H₂O₂) and anti-inflammatory activities, with the highest activity observed at 500&#xa0;µg/mL. These findings highlight the potential of <i>S. trilobatum</i> as a promising candidate for OSF therapy, but warranting further experimental studies.</p>