The aim of this work was to apply an experimental design to formulate a stable depilatory cream at ambient temperature. A preliminary study was performed to optimize the most accurate operating parameters, which are then used for the determination of the rheological properties. Long-term stability of the emulsion formulations was investigated to obtain the optimal region of each factor. An experimental design using response surface modelling was then applied and emulsion stability was estimated by introducing new characteristic parameters correlated with the experimental results. An optimal region characterized with high stability was found and further explored to verify the effectiveness and tolerance of depilation. As part of the optimized process, the main effects of the formulation ingredients were also investigated.