Cilostazol, an anti-platelet aggregation medicine, is also known to have vasodilation properties and is commonly used for treating muscle soreness and cramps by increasing the muscle oxygen supply. The medication has limited oral bioavailability, is prone to pre-systemic metabolism, and is poorly soluble in aqueous media. A transdermal administration was planned to increase the drug’s solubility and therapeutic efficacy. The current work intended to develop cilostazol niosome-loaded transdermal gel, which was prepared, and with the use of Fourier transform infrared and differential scanning calorimetry analyses, drug-excipient interactions were observed. The medication was formulated utilizing Carbopol-934, Pluronic-F-127, and HPMC gel bases for the transdermally delivered niosomal gels. The produced niosomes had a maximum percentage of drug entrapment at 96.4%, with a particle size of 102 ± 11.30 nm and polydispersity index of 0.29 ± 0.069. The highest percentage of the medication that was entrapped was 96.4%, and the Carbopol-934 gel basis released the major part of the drug under in vitro conditions. A maximum transdermal flux was recorded at 3850.92 μg after 4 h, indicating a 10% increase in cilostazol permeation through rat skin. The flux rate for the niosomal preparation containing the drug ranged from 14.85 to 28.02 μg/cm2 h−1. In comparison to the pure cilostazol-loaded gels, the pharmacokinetics investigation showed that the niosomal gel formulations had considerably greater C max, T max, and AUC0. The niosomes loaded with cilostazol exhibited greater solubility, higher bioavailability, and improved effectiveness. Better therapeutic results may be achieved with systemic and site-directed delivery of cilostazol using the designed transdermal niosomal gel with appropriate molecular tagging modification/(s).