Diesel exhaust particles (DEPs) are major air pollutants that lead to numerous human disorders, especially pulmonary diseases, partly through the induction of oxidative stress. Resveratrol is a polyphenol that ameliorates the production of reactive oxygen species (ROS) and delays aging-related processes. Herein we studied the cytoprotective effect of resveratrol on DEP-exposed human lung cells in a factorial experimental design. This work investigates biophysical features including cellular compositions and biomechanical properties, which were measured at the single-cell level using confocal Raman microspectroscopy (RM) and atomic force microscopy (AFM), respectively. Principal component analysis (PCA), hierarchical cluster analysis (HCA) and partial least square regression (PLS) analysis were applied to analyze Raman spectra with and without resveratrol protection. The health status of individual cells could be effectively predicted using an index derived from characteristic Raman spectral peak (e.g., 1006 cm-1) based on PLS model. AFM measurements indicated that cellular adhesion force was greatly reduced, while Young's modulus was highly elevated in resveratrol treated DEP-exposed cells. Anti-oxidant resveratrol reduced DEP-induced ROS production and suppressed releases of several cytokines and chemokines. These findings suggest resveratrol may enhance resistance of human lung cells (e.g., SAEC) to air pollutants (e.g. DEPs).