Abstract Recent advances in modern medicine emphasize patient-centric and personalized therapeutic strategies, particularly for chronic and regenerative applications. Among emerging biomaterials, chitosan (CS) has gained considerable attention due to its biocompatibility, biodegradability, and antimicrobial properties, while its molecular weight strongly influences structural organization and interactions with active compounds. In this study, chitosan-based matrices—2% (w/v) low-molecular-weight CS, 4% (w/v) low-molecular-weight CS, and 2% (w/v) medium-molecular-weight CS—were developed and enriched with ibuprofen (IBU), a widely used non-steroidal anti-inflammatory drug, to improve topical delivery and reduce systemic side effects. The physicochemical properties of gelled thin films were investigated with emphasis on molecular arrangement, surface characteristics, and drug release behavior in phosphate-buffered saline. ATR-FTIR spectroscopy, contact angle measurements, and atomic force microscopy (AFM) were employed to evaluate structural and functional changes induced by IBU incorporation. Medium-molecular-weight CS exhibited lower water contact angles (≈69–73°) and higher surface free energy (≈41–44 mN m−1) compared to low-molecular-weight CS, while IBU loading did not significantly alter wettability. AFM analysis revealed drug-induced surface roughness changes, with Ra increasing from 23.9 nm (2CS_M) to 29.4 nm after IBU loading and further to 35.5 nm following release. ATR-FTIR spectra confirmed preservation of characteristic chitosan amide I and II bands (∼1645 and ∼1556 cm−1), with spectral changes in the 1450–1700 cm−1 region indicating interactions between IBU and CS functional groups. Among the investigated systems, 2% (w/v) medium-molecular-weight chitosan demonstrated the most favorable sustained IBU release (∼50% after 48 h), highlighting its potential for dermal drug delivery and personalized therapeutic applications.