Background: The evaporation of volatile ingredients from topical formulations strongly influences transdermal permeation and overall bioavailability, yet coupled evaporation–permeation dynamics are mostly simplified or neglected in existing models. Methods: We developed a mechanistic framework that couples Fickian gas-phase evaporation and transdermal permeation, both driven by the activity coefficients of volatiles. The model equations are implemented in a hybrid MATLAB–Python architecture with the volatile activity computed on-the-fly using UNIFAC and the gas-phase diffusivity calculated by the kinetic equation of Fuller–Schettler–Giddings (FSG). Initial validation used published IVPT data for 4-Tolunitrile and Nitrobenzene. Results: For 4-Tolunitrile, the FSG-based model estimated an initial evaporation coefficient of K_evap,i = 7.9348 × 10⁻¹⁰ mol·cm⁻²·s⁻¹, and parameter optimization converged to 8.3929 × 10⁻¹¹ mol·cm⁻²·s⁻¹ (≈1/10 of the FSG estimate). The optimized model predicted an accumulation amount of 19.15% versus an experimental value of 16.97% in the receptor fluid (RF) at 24 h. For Nitrobenzene, the FSG initial estimation value of K_evap,i = 6.6480 × 10⁻¹⁰ mol·cm⁻²·s⁻¹ was optimized to 8.1174 × 10⁻¹¹ mol·cm⁻²·s⁻¹ (≈1/8 of the FSG value), and the predicted amount of 24 h RF is 27.61% (experimental 23.19%). Both optimized K_evap,i values are roughly one order of magnitude lower than the initial FSG estimates, but >20× larger than Stokes–Einstein (SE)-derived values. Sensitivity scans show that further tuning of internal skin parameters (e.g., diffusion coefficient (D_SC,i) and partition coefficient (P_SCw,i)) produced only marginal improvements in RF prediction once K_evap,i was optimized. Conclusions: The coupled evaporation–permeation framework reproduces key IVPT kinetics for volatile solutes when the effective evaporation coefficient is calibrated. The kinetic-theory estimates (FSG-based) are a reasonable starting point, but typically overestimate the evaporation rate constant under finite-dose unoccluded IVPT conditions. By implementing the on-the-fly computation of volatile activity using UNIFAC, the approach is extensible to modelling transdermal permeation of volatiles from multicomponent/non-ideal formulations.