Reverse osmosis (RO) membrane materials play a key role in determining energy consumption. Currently, CTA is regarded as having one of the highest degrees of chlorine resistance among materials in the RO process. The hollow fiber membrane has the advantages of a large membrane surface area and a preparation process without any redundant processes. Herein, response surface methodology with Box-Behnken Design (BBD) was applied for optimizing the preparation conditions of the cellulose triacetate (CTA) hollow fiber RO membrane. There were four preparation parameters, including solid content, spinning temperature, post-treatment temperature, and post-treatment time, which could affect the permeability of the membrane significantly. In this study, the interaction between preparation parameters and permeability (permeate flux and salt rejection) was evaluated by regression equations. Regression equations can be applied to obtain the optimized preparation parameters of hollow fiber RO membranes and reasonably predict and optimize the permeability of the RO membranes. Finally, the optimized preparation conditions were solid content (44%), spinning temperature (167 °C), post-treatment temperature (79 °C), and post-treatment time (23 min), leading to a permeability of 12.029 (L·m-2·h-1) and salt rejection of 90.132%. This study of reinforced that CTA hollow fiber membrane may promote the transformation of the RO membrane industry.