Amlexanox-loaded electrospun nanofibers were investigated as a buccal drug-delivery system for local management of aphthous ulceration. Amlexanox was a pale-yellow crystalline, odourless, metallic-tasting powder and showed a practical melting point of 333.0 °C. UV spectrophotometric analysis in phosphate buffer pH 6.8 showed λmax at 244 nm. PVA, PVP K30 and PVP K90 were screened by preliminary electrospinning trials. Drug-loaded PVP K30 did not sustain Taylor-cone formation, whereas PVP K90 supported drug-loaded electrospinning; A29 and A30 showed prolonged Taylor-cone formation and drug entrapment of 73.57% and 76.84%, respectively. A two-factor, three-level optimization study evaluated PVP K90 concentration and tip-to-collector distance. For AF1–AF10, entrapment efficiency ranged from 70.4±2.3% to 81.6±2.0%, 12-h cumulative diffusion from 47.32% to 83.73%, and 24-h cumulative diffusion from 82.16% to 97.82%. The quadratic model for entrapment efficiency was significant (F=9.15, p=0.0260; R²=0.9196). AF11 showed 59.70% diffusion at 12 h and 91.58% at 24 h. The experimental dataset demonstrates the feasibility of PVP K90-based amlexanox nanofibers, while the coded-versus-actual optimization matrix and prospective stability study require reconciliation/completion before definitive optimized-product claims.