Nuclear receptor-binding SET domain protein 3 (NSD3) plays an important role in the initiation and progression of lung squamous cell carcinoma (LUSC), whereas small-molecule inhibitors targeting NSD3 remain limited. This study targeted the NSD3-PWWP1 domain and identified 37 potential NSD3-binding compounds through Glide-based hierarchical virtual screening followed by drug-likeness filtering. Surface plasmon resonance (SPR) analysis showed that compounds 2, 4, 20 and 27 could directly bind to NSD3, among which compound 2 exhibited the strongest equilibrium dissociation constant (K_D = 0.95 μmol·L^-1), approaching that of the positive control BI9321 (0.46 μmol·L^-1). Molecular docking analysis indicated that all four candidate compounds could occupy the NSD3-PWWP1 binding pocket and form stable interactions with key residues. At 30 μmol·L^-1, the four candidate compounds showed different degrees of inhibitory activity against three NSD3-high LUSC cell lines. Notably, compound 2 displayed a half maximal inhibitory concentration (IC₅₀) of 4.08 ± 1.01 μmol·L^-1 in HCC95 cells, which was superior to that of BI9321 (17.62 ± 3.11 μmol·L^-1). Meanwhile, these candidate compounds did not show obvious cytotoxicity toward HEK293T cells and exhibited favorable ADMET profiles and physicochemical property distributions. In conclusion, several potential NSD3 inhibitors were identified in this study. Among them, compound 2, a novel coumarin-based scaffold distinct from BI9321, represents a promising lead for further optimization as an anti-LUSC agent.