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Aims: To optimize, formulate, and evaluate a Nanostructured Lipid Carrier (NLC) based transdermal gel of Etodolac (ETD). Objective: To avoid issues of conventional route ETD administration like first pass metabolism, gastric ulceration, hemorrhage, and being a class-II drug with less solubility. A transdermal gel of nanostructured lipid carrier for ETD has been developed. Formulation will execute faster onset of action, increased penetration, permeation with extended release of the drug for a longer duration. Methods: A central composite 32 factorial design is used to plan experiments. NLCs are prepared by the method of melt emulsification and ultrasonication. Compritol 888ATO and Miglyol are used as solid and liquid lipid phases. Surfactant Pluronic F68 showed a significant effect on particle size, entrapment efficiency, and drug release. Particle size characterized using photon correlation spectroscopy and scanning electron microscopy. Cumulative drug release studied using an artificial diffusion cell and a dialysis membrane. A skin permeation study was performed using goat skin at 32°C ± 0.5°C. The efficacy of the NLC gel was verified using a pharmacodynamic study followed by stability study for 3 and 6 months. Results: The optimized batch of ETD NLC found spherical with a 241.3 nm particle size with 0.392 PDI,-29 mV zeta potential. Entrapment efficiency and cumulative drug release were found to be 64.21 ± 1.23% and 70.12 ± 2.10% (after 12 hours), respectively. All batches followed zeroorder drug release kinetics and non-Fickian (Super Case II transport) with 0.1619 mg/cm2/hr transdermal flux. The NLC gel of ETD showed a quick onset and lengthened therapeutic activity until 24 hours compared to the micellar ETD gel. Conclusion: Etodolac NLC batch successfully optimized using central composite design. The relationships between the components of the NLC-total lipid:drug and surfactant-and the outcomes- particle size,%entrapment and% drug release-were better understood by examining several contour plots. The results of the experimental and predicted formulations were found to be in good agreement with slight bias, demonstrating the reliability of the optimization process.