The efficiency of the textile hot air-drying process fundamentally requires the uniformity of the airflow that impinges on the textile fabric. Optimization of a stenter machine’s hot air supply chamber shape was conducted in this paper, based on the actual real-size model and considering both the outlet flow uniformity and the standard velocity deviation as responses. The purpose is to improve the airflow uniformity at the chamber outlet, and modifications applied to the baseline must be applicable to both old and next-generation stenter machines. Coupled Computational Fluid Dynamics and Design of Experiment (CFD-DoE) optimization on the stenter machine chamber geometry was carried out. The CFD model was validated by measuring the chamber outlet velocity using a 2D velocity scanner. After choosing seven factors based on mechanical manufacturing and fluid dynamics theories, a main effect screening design was conducted to highlight relevant factors that influence the outlet airflow distribution. By fixing the best categorical factors, a central composite design (CCD) was applied using three other continuous factors to generate a quadratic prediction model that could be used to simultaneously maximize and minimize the uniformity index (UI) and the standard deviation (SD), respectively. With the embedded JMP SAS desirability function, the optimal value was calculated based on a statistical approach. Those values were used to design an optimal stenter air supply chamber that has been simulated with Fluent CFD code to validate the statistical prediction model. Finally, optimized geometry was obtained and experimentally validated. Results show that this new chamber improved by 16.48% for the uniformity index and 38.07% for the standard deviation.