Indomethacin is a nonselective nonsteroidal anti-inflammatory drug with serious side effects such as depression, hallucination, and gastrointestinal irritation. This study aims to enhance indomethacin lipid solubility of indomethacin derivative to use it for the topical formulation since topical formulation may lower the unwanted side effects. The lipid solubility was achieved by adding various alkyl groups (methyl, ethyl, propyl, and isopropyl) to the drug via an ester linkage. The measured log p of these compounds was higher compared to the underivatized indomethacin. Furthermore, an ointment of each ester was formulated and was tested on mice skin using Franz diffusion. The best absorption was observed for methyl indomethacin with threefold increase in permeability compared to indomethacin. This study approves using derivatized indomethacin as a topical formulation with improved efficacy compared to the present gel formulation in the market.