Losartan potassium (LP) is an angiotensin II receptor blocker (ARB) with established clinical utility in the management of hypertension and diabetic nephropathy. Oral delivery of LP is hampered by extensive hepatic first-pass metabolism and highly variable bioavailability (25–35%), making it a compelling candidate for transdermal administration. The stratum corneum, however, presents a formidable physicochemical barrier that restricts passive permeation of most drug molecules. The present study describes the development and comprehensive physicochemical characterization of LP-loaded ethosomes elastic, ethanol-enriched phospholipid vesicles—incorporated into a hydroxypropyl methylcellulose (HPMC K100M)-based matrix transdermal patch. Six ethosomal formulations (EP-1 to EP-6) were prepared by the cold-membrane extrusion method by systematically varying phosphatidylcholine (300–400 mg), cholesterol (75–100 mg), and ethanol content (20–40% v/v). The optimized formulation (EP-6) displayed a mean particle size of 176.3 ± 3.9 nm, a polydispersity index of 0.241 ± 0.01, a zeta potential of −34.8 ± 1.2 mV, and an encapsulation efficiency of 85.7 ± 1.5%. Ethosomal vesicles were incorporated into a solvent-cast HPMC matrix patch demonstrating acceptable physicochemical attributes including tensile strength (4.8 ± 0.3 N/mm²), moisture content (3.2 ± 0.4%), and drug content uniformity (97.8 ± 0.9%). In vitro membrane permeation studies performed using Strat-M® synthetic membrane a well-validated, animal-free surrogate for human skin—demonstrated a steady-state flux of 62.4 ± 2.3 µg/cm²/h for the EP-6 patch, representing a 4.3-fold enhancement over a conventional matrix patch. Release kinetics conformed to an anomalous (non-Fickian) diffusion model. Confocal laser scanning microscopy using fluorescently labeled ethosomes confirmed deep penetration through the Strat-M® membrane layers, validating the mechanistic basis of the observed permeation advantage. Stability evaluation under ICH Q1A(R2)-prescribed conditions demonstrated that the patch retained physicochemical integrity over six months. These results collectively support the viability of an LP ethosomal transdermal patch as a controlled, animal-free-validated delivery platform for antihypertensive therapy.