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In the present work, an experimental investigation and mathematical modeling of tomato waste hot air drying (HAD) were conducted for drying temperatures of 50 and 60°C, and air velocities of 1 and 2 m s−1. Kinetics, mathematical modeling, and optimization of biological properties using response surface methodology (RSM) were investigated. Increasing the drying temperature from 50 to 60°C shortened the drying time by 5 and 20 min, respectively, for 1 and 2 m s−1 air velocities. The proposed mathematical model with the highest correlation coefficient of 0.9997 well described the moisture variation of tomato waste. Significantly high diffusivity was observed with values of 1.24 × 10−6 and 1.67 × 10−6 m2 s−1. Obtained analysis showed an increase in polyphenol (PPT) and flavonoids (TFC) and a decrease in lycopene content (LYC) and ascorbic acid (AA). Phenomenological modeling and RSM methodology indicated that both drying temperature and air velocity affected the content of TFC, LYC, and AA, whereas, for PPT, the temperature has a positive effect in contrast with negative of air velocity. Optimum drying time, PPT, TFC, LYC, and AA are 44.6 min, 227 mg GAE/g, 32.2 mg GAE/g, 517.92 mg/100 g, and 1.91 mg AAE/100 g, respectively. Optimal drying temperature and velocity were, respectively, 56.7°C and 1 m s−1. [ABSTRACT FROM AUTHOR]