Clarithromycin (CLR), categorized as a Biopharmaceutical Classification System class II drug, has several gastrointestinal tract side effects and an extremely unpalatable bitter taste. The current study aimed to design transdermal patch-embedded CLR niosomes to overcome the aforementioned CLR-related challenges. Various niosomal formulations were successfully fabricated and characterized for their morphology, size, in vitro release, and antimicrobial efficacy. Subsequently, the CLR niosomes were loaded into transdermal patches using the solvent casting method. The polydispersity index of the niosomes ranged from 0.005 to 0.360, indicating the uniformity of the niosomes. The encapsulating efficiency (EE)% varied from 12 to 86%. The optimal Chol: surfactant ratio for drug release was found to be 0.5:1. In addition, the encapsulation of CLR into niosomal nanovesicles did not reduce the antibacterial activity of the CLR. The niosomal patch had a significantly higher permeability coefficient of CLR than the conventional patch. In addition to that, a shear-thinning behavior was observed in the niosomal gels before loading them into a niosomal patch. The flux (Jss) of the niosomal patch was significantly higher than the conventional patch by more than 200 times. In conclusion, niosome-based transdermal patches could be a promising method for the transdermal drug delivery of class II drugs and drugs experiencing GIT side effects.