Sulfur compound content in fuels is one of the most undesirable pollutions regarding standard environmental regulations that demand to reduce sulfur concentration limit to 5-10% in fuels. Hence, kerosene’s oxidative desulfurization (ODS) as a model fuel (sulfur content 1158ppm) with air as an oxidant is studied. The goal of the study is to use two different synthesized nanosilica-supported catalysts, CuO/SiO2 (CAT-1) and CuO/TiO2-SiO2 (CAT-2), for the ODS of kerosene. Thirty-two experimental runs were designed via Central Composite Design (CCD) to select the experiments that will be utilized most efficiently. The analysis of variance (ANOVA) was used for statistical analysis to determine the models’ significance. The Response surface methodology (RSM) was used to determine the optimum conditions and parameters significantly affecting the response. Temperature and time are two variables studied due to their impact on oxidative desulfurization. The actual results of sulfur conversion in kerosene from lab experiments were 87% with a sulfur content of 153.3ppm and 99.22% with a sulfur content of 8.9ppm by CAT-1 and CAT-2, respectively, at conditions of 140°C and 100min. The predicted results from experimental design were 86.66% and 99.8% by CAT-1 and CAT-2 at conditions of 140°C and 100min, showing errors less than 3.1% and 1.2% for CAT-1 and CAT-2, respectively, from ANOVA. The optimal parameters of ODS were determined through the sulfur conversion maximization by numerical optimization via ANOVA. The results showed that the maximum conversion by CAT-1 was 99.5% at 140 min and 180°C, and by CAT-2 was 99.7% at 100.1 min and 140.1°C. Also, the rate data were fitted with an empirical kinetic model. The results showed that CAT-1 and CAT-2 activation energies were Ea= 28.2 kJ/mol and Ea= 38.7 kJ/mol, respectively.