The current study focuses on development of phospholipid complex-loaded films of etodolac for enhanced transdermal permeation and anti-inflammatory effect. An etodolac-phospholipid complex was developed using the solvent evaporation method and was characterized by DSC, XRD, FTIR, and 1H-NMR studies. The formation of the complex led to conversion of a crystalline drug to an amorphous form. A stoichiometric ratio of 1:1 (drug-phospholipid) was selected as the optimized ratio. Further, the developed complex was incorporated into films and systematic optimization using a central composite design was carried out using a response surface methodological approach. The desirable design space based on minimum contact angle and maximum tensile strength was selected, while the water vapour transmission rate and swelling index were set within limits. The results for swelling index, contact angle, tensile strength, and water vapour transmission rate were 60.14 ± 1.01%, 31.6 ± 0.03, 2.44 ± 0.39 kg/cm2, and 15.38 g/hm2, respectively. These values exhibited a good correlation with the model-predicted values. The optimized formulation exhibited improved diffusion and permeation across skin. In vivo studies revealed enhanced anti-inflammatory potential of the developed films in comparison to the un-complexed drug. Hence, the study demonstrated that etodolac-phospholipid complex-loaded films improve the transdermal permeation and provided enhanced anti-inflammatory effect.