Mebeverine hydrochloride (MBH) is an antispasmodic drug that holds the potential to exert a local anesthetic action via blocking voltage operated sodium channels. However, its local anesthetic activity was not yet exploited due its poor skin permeability. Nanocarriers have emerged as efficient vehicles for delivering both lipophilic and hydrophilic drugs through the stratum corneum. In this study, therefore, the efficacy of ethosomes for delivering MBH via skin for local anesthetic effect was investigated. The ethosomes were formulated, optimized and characterized for particle size, zeta potential, entrapment efficiency and in vitro permeation studies. Then, the optimized formula was incorporated into Carbopol 940® gel and evaluated for skin irritation and in vivo local anesthetic action. Ethosomes were spherical in shape with vesicle sizes varied from 308.2 ± 18.2 nm to 78.8 ± 8.6 nm and entrapment efficiencies of 18–65%. In vitro drug permeation across rabbit ear skin revealed enhanced drug permeation and higher transdermal flux with ethosomal formulations, compared to aqueous drug solution. In addition, an ethosomal gel of optimized formula showed a potent local anesthetic effect as manifested by a 2.3-fold increase in the area under the efficacy curve (AUEC) of MBH loaded ethosomal gel, compared to the MBH gel. Furthermore, skin irritation experiments demonstrated that MBH ethosomal gel induced neither erythema nor edema upon application to rabbit skin. Collectively, MBH loaded ethosomal vesicles might represent a promising delivery vehicle for safe and efficient local anesthetic effect