The aim of the present study was to determine impacts of different additives on fatty acid composition and total tocopherol content of cottonseed oil during deep-frying process using a chemometric approach. A quarter-fractional factorial design with two levels and five factors was used for preparing the frying cottonseed oil blends. In the experimental design, additives were such as ascorbic palmitate, mixed tocopherols, dimethylpolysiloxane, lecithin, and sesame oil were used as factors. The effect of additives on fatty acid composition and tocopherol content were evaluated with normal distribution (ND) graphs during ten hours frying at 170 ± 5°C. The data were statistically assessed by one-way analysis of variance at a significance level of p < 0.05. The analysis of variance test results were in good agreement with ND graphs and data indicated that the interaction between ascorbic palmitate and dimethylpolysiloxane (A × C factor) showed a significant and protective effect on fatty acids. Meanwhile, the sesame oil (E factor) and A × C factor were showed a significant effect on level of tocopherols. The results of study indicated that present approach could be used to assess and improve the frying stability of any oil with respect to fatty acid composition and tocopherols.