The present study aimed to formulate and evaluate a stable water-in-oil (W/O) topical cream containing niacinamide and hexylresorcinol for anti-inflammatory and dermatological applications. Preformulation studies including organoleptic evaluation, solubility analysis, melting point determination, and drug–excipient compatibility (FTIR) were conducted to ensure suitability of the selected ingredients. Three formulations (F1, F2, and F3) were prepared using appropriate emulsifying agents and evaluated for physicochemical parameters such as pH, homogeneity, spreadability, viscosity, washability, stability, and microbial load. In vitro anti-inflammatory activity was assessed using the protein denaturation assay with bovine serum albumin. All formulations exhibited acceptable physical characteristics, pseudoplastic flow behavior, good spreadability, and absence of phase separation. Microbial load testing confirmed microbiological safety. Among the developed formulations, F2 demonstrated superior stability and the highest inhibition of protein denaturation (68.9 ± 1.0%), comparable to standard diclofenac (72.5 ± 0.8%). The results indicate that the optimized W/O cream formulation possesses desirable physicochemical, microbiological, and biological properties and may serve as a promising topical preparation for inflammatory skin conditions.