Dermal application of various active substances is widely preferred for topical or systemic delivery. SLNs are consisting of biocompatible and non-toxic lipids and have a great potential for topical application of drugs. In this study, semisolid SLN formulations were successfully prepared by a novel one-step production method as a topical delivery system of an anti-inflammatory drug, etofenamate. Compritol 888 ATO and Precirol ATO 5 were chosen as lipid materials for the fabrication of the formulations. In-vitro evaluation of the formulations was performed in terms of encapsulation efficiency, particle size, surface charge, thermal behavior, rheological characteristics, in vitro drug release profile, kinetics, mechanisms, stability, and anti-inflammatory activity. The colloidal size and spherical shape of the particles were proved. According to the results of rheological analysis, it was demonstrated that the semisolid SLN formulations have a gel-like structure. Stability studies showed that semisolid SLNs were stable at 4°C for six months period. Zero order release was obtained with Precirol ATO 5, while Compritol 888 ATO followed square root of time (Higuchi's pattern) dependent release. Semisolid SLNs were shown higher inhibitory activity of COX in comparison with pure etofenamate. In conclusion, etofenamate loaded semisolid SLN formulations can be successfully prepared in a novel one-step production method and promised their use for topical application