The transdermal route has received a lot of attention and has established itself as a reliable substitute to address the shortcomings of drug delivery via the oral and parenteral routes. However, the stratum corneum (SC), the skin's top layer that functions as a barrier to drug diffusion, frequently reduces the efficacy of TDDS. The drug's molecular weight, hydrophilicity, and ionic makeup can also affect how effectively it is delivered transdermally. Nano-carriers, wearable delivery devices, and combination-based strategies are just a few of the techniques that have been developed to get beyond these restrictions and enable medication penetration across the SC. Nano-carriers including dendrimers, liposomes, niosomes, and micro sponges have the potential to improve TDDS's effectiveness. Wearable delivery systems, which provide non-invasive, practical, and extended drug administration, are another new development for TDDS. The focus of interest in the study of TDDS technologies is combination-based approaches, such as ultrasound and microneedle-based systems or ultrasound and electrical-based techniques. This review enumerates all unique penetration enhancement methods that have been employed to improve the efficacy of transdermal drug delivery systems but which have not been fully covered by prior review papers. These penetration augmentation approaches were emphasised separately in the majority of review papers. But there isn't a comprehensive analysis of all the penetration augmentation methods in one piece. Therefore, the goal of this paper is to thoroughly examine and summarise in one article the most recent penetration augmentation approaches as well as any potential mechanisms of action. Our main goal is to gather pertinent reviews and research articles through the use of numerous databases in order to present a thorough overview of the topic. This review article will assist students and researchers keep current with the most recent advancements in the field of innovative penetration enhancement strategies used to increase the efficiency of TDDS by giving a thorough overview of the existing techniques.