Background: The Transdermal drug delivery system (TDDS) was created to enhance drug release sustainability, increase drug bioavailability, and improve patient compliance. Matrix dispersion transdermal patches distribute the drug in a solvent with polymers, and then the solvent evaporates to create a uniform drug-polymer matrix. The aim of this study was to create and develop transdermal drug delivery systems (TDDS) containing granisetron hydrochloride and assess its prolonged release in laboratory conditions. Materials and Methods: The study aims to develop a matrix-type transdermal treatment system that includes granisetron hydrochloride using different ratios of hydrophilic and hydrophobic polymer combinations through the solvent evaporation process. Results: Fourier transform infrared spectroscopy was employed to investigate the physicochemical compatibility of the drug with the polymers. The results showed that there was no physical-chemical incompatibility between the drug and the polymers. The patches were subjected to further physical evaluations and in-vitro permeation studies. Conclusions: The patches containing Carbopol 934P and ethylcellulose, along with span 80 as the penetration enhancer, were identified as the most effective formulations for transdermal delivery of granisetron hydrochloride based on physical evaluation and in-vitro studies.