Ionic liquid-in-oil (IL/o) microemulsion (ME) techniques have been employed to increase the solubility of sparingly soluble drugs and enhance the extent of their topical and transdermal delivery. Methotrexate (MTX) has been used as a model drug in the current study. The size and size distributions of the ME droplets in the presence and in the absence of MTX were determined by dynamic light scattering analysis. The mean droplet diameter of the ME droplets containing 4 mg/mL of MTX was less than 20 nm, and smaller than the corresponding value observed in the absence of MTX. MTX was incorporated into IL droplets as well as other formulations and its permeation across Yucatan micropig (YMP) porcine skin evaluated. The use of IL/o ME has been shown to dramatically increase MTX administration. The results obtained in this study reveal the versatility of IL/o MEs as efficient drug delivery systems for sparingly soluble drugs.