Background: Curcumin (CUR) is a well-known herbal constituent used in treating psoriasis. However, combination of CUR with other anti-inflammatory drugs such as caffeine shows amplified antipsoriatic action compared to CUR alone. Objective: The objective of the present study was to develop nanostructured lipid carriers (NLCs)-based topical gels of CUR and caffeine combination for facilitated treatment of psoriasis. Materials and Methods: Preparation of NLC's loaded with CUR and caffeine was done by hot homogenization and ultrasonication methods and incorporated in topical gels. Factorial design (32) was constructed in a fully randomized manner to formulate and evaluate all nine possible experimental runs. Detailed evaluation studies for NLC and NLC-based gels were conducted. In vivo animal studies were carried out for optimized formulation using mouse model of imiquimod-induced psoriasis. Results: The physical and chemical characteristics displayed by the prepared NLC's (F1–F9) and gels were found to be optimal. The optimization using experimental design approach resulted in achieving formulation F10 with 103.01 nm particle size and 61.52% entrapment efficiency. In vivo and histopathology studies revealed that prepared NLC-based gel exhibits promising antipsoriatic activity. Conclusion: The present study signified that the CUR and caffeine combination has better antipsoriatic activity. Moreover, NLC-loaded gels have provided sustained drug release till the end of 12 h.