Transdermal Drug Delivery Systems (TDDS) offer a non-invasive method of administering drugs through the skin and straight into the bloodstream, which is a significant development in contemporary pharmaceutics. This method keeps plasma levels constant, prevents first-pass metabolism, and increases patient compliance. To ascertain TDDS's effectiveness, safety, and stability, however, an assessment is necessary because the stratum corneum serves as a strong barrier. In-vitro, ex-vivo, and in-vivo approaches are among the several methods of TDDS assessment that are thoroughly reviewed in this article. There is also discussion of pharmacokinetic, analytical, and safety evaluation factors. Each method's benefits, drawbacks, and prospects for the future are critically outlined, highlighting their importance in the development of logical formulations and regulatory clearance.