The advantages of hot-melt extrusion technology (HME) over conventional techniques to develop topical semisolids have been established. However, this technique is not widely used for semisolid production. Therefore, the aim of this novel work was to develop creams using the melt extrusion technology while applying Quality by Design (QbD) principles to study the effects of the extrusion process parameters on the product characteristics. The model drug selected was hydrocortisone acetate. A 23 factorial design was considered for the factor influence study, which resulted in eight formulations to be extruded. Of the process parameters considered, the temperature of zone 2 had a significant influence on the work of adhesion of the creams. A similar permeation profile was obtained for all the formulations with the formulations following a diffusion based drug release mechanism. The results from the size distribution graph indicated stable cream formulations. In conclusion, this technology coupled with a design of experiments approach could be utilized to study how the extrusion process parameters could be modified to develop consistent topical creams with ideal product characteristics.