Purpose <p>Tenofovir disoproxil is a drug used to treat chronic hepatitis as well as HIV/AIDS prevention for the skin or the mucous membrane. Here, a 2³ factorial design for the tenofovir emulgel formulation was chosen, exhibiting 13 experimental runs (five central points) constructed using Design Expert software.</p> Methods <p>The prepared emulgels were prepared by employing MethocelK100LV, Kolliphor-p188 and glycerol. To find physical appearance, spreadability, pH, washability, in-vitro dissolution, ex-vivo diffusion, in-vitro intestinal permeability, polydispersity index, particle size, zeta potential, drug release kinetics, and drug-excipient compatibility studies.</p> Results <p>The FTIR and DSC investigations revealed no interactions between tenofovir and the various excipients used. The product is easy to spread and wash, and no skin sensitivity has been noted. The order of drug dissolution in various formulations is illustrated as E5 &lt; E7&lt; E6 &lt; E10&lt; E1 = E3=E4 = E8=E11 = E12=E13 &lt; E9&lt; E2. The E5 formulation follows Higuchi diffusion, and diffusion exponents less than 0.5 suggest Fickian diffusion. Ex vivo diffusion tests were performed to optimize formulation E5 using sheep skin, resulting in 100% drug release within 6.0&#xa0;h of diffusion. The drug release has zero-order kinetics (r² = 0.8741) and Fickian diffusion (<i>n</i> = 0.2597). In vitro intestinal permeability studies were conducted to optimize formulation E5 utilizing sheep intestine (T100) for 100% drug release in 5.0&#xa0;h. The medication is released through Higuchi diffusion (r2 = 0.8831) and non-Fickian diffusion (<i>n</i> = 0.6923). The particle size of the emulgel formulation (E5) was found to be 244.3&#xa0;nm, with a polydispersity index of 0.113. This revealed a relatively homogeneous dispersion, with formulation E5 having a zeta potential of -43.1mv. The ANOVA of the time required for 100% drug release (T100) was statistically significant (<i>p</i> &lt; 0.0078).</p> Conclusion <p>The emulgel formulations have been reviewed for quality by design approach, factorial design with software tools to identify significance.</p>