The transdermal route of drug delivery has gained immense interest from pharmaceutical researchers. The major hurdle for the diffusion of drugs and bioactive through the transdermal route is the stratum corneum, the outermost layer of the skin. Currently, various approaches such as the physical approach, chemical approach, and delivery carriers have been used to augment the transdermal delivery of bioactive. Materials and Method With the use of the Box-Behnken Design, thirteen formulations were created by altering the amounts of ethanol, soy lecithin as a lipid, and the lipid: span ratio. Vesicle size, entrapment effectiveness, drug retention, drug permeability through the skin, and shape were attributes of the optimized formulation. Result and Conclusion The Results demonstrated the successful fabrication of the curcumin-loaded polymeric nanotransethosomes. Gels with improved CRM-TE were added, and a side-by-side analysis was done. The 180-day storage of CRM-TE gel at 5°C, 25°C, and 40°C was followed by an evaluation of its entrapment effectiveness and vesicle size. At 24 hours in the skin, CRM-TE revealed 286.4 nm vesicle size, 64.2% entrapment efficiency, 19.8% drug retention, and 71.3% drug permeation. Additionally, CRM-TE gel demonstrated the greatest qualities in terms of drug penetration, drug retention, and entrapment effectiveness CRM-TE gel showed higher stability at 5–3°C in terms of vesicle size and entrapment effectiveness gel could provide effective topical administration of curcumin.