The objective of the research was to develop and evaluate niosomal preparations of diclofenac sodium with the view of enhancing transdermal drug delivery in animals. Niosomes were prepared using thin-film hydration technique, which is based on non-ionic surfactants and vesicle, and they were characterized based on particle size, zeta potential, entrapment efficiency, and morphology. The performance of the formulations was calculated in comparison to conventional gel by undertaking ex vivo skin permeation test in rat skin and in vivo pharmacokinetic test on Wistar rats. Findings showed that niosomal preparations and specifically Niosome F3 had a smaller particle size, greater entrapment efficiency, and better stability which resulted in a significant enhancement of skin permeation and the sustained system levels of absorption. Ex vivo experiments revealed that optimized niosomes had almost twice the drug permeation rate versus conventional gel whereas in vivo experiments revealed improved peak plasma concentrations and increased drug retention. These data confirm the hypotheses suggested and indicate that niosomal carriers are an appropriate method of overcoming the barrier of stratum corneum, increasing drug delivery, and achieving controlled release. The research emphasizes the opportunities offered by niosomal formulations as a flexible and effective carrier of transdermal drugs delivery, as a method to enhance the therapeutic effect, the efficiency of the dosing schedule, and minimize the side effects experienced by the system.