This study investigates the correlation between the hydrophilic–lipophilic balance (HLB) values and the π–A isotherm parameters of surfactant monolayers composed of sorbitan esters, specifically sorbitan monopalmitate, sorbitan tristearate, sorbitan monooleate, and sorbitan sesquioleate. The surfactant mixtures were prepared, and their π-A isotherms were recorded. The HLB values calculated for each mixture were in the range 2.10–6.70. The HLB values were compared to compression parameters, including the ratios of the slopes and the ratios of the intercepts, which were between 0.19 and 4.00 and between 0.64 and 1.77, respectively, across the monolayer compression stages. The findings indicate a significant relationship between HLB values and isotherm parameters, particularly for systems with sorbitan monooleate and sorbitan sesquioleate. A value of determination coefficient of 0.95 was found for the linear equation representing the slope ratios as a function of HLB, whereas the intercept ratios, as a linear function of HLB, gave a lower value of 0.71. The results allow for the use of the π–A Langmuir isotherm to experimentally estimate the value of the HLB in mixtures of the sorbitol esters of fatty acids, whose value is an important parameter in the selection of optimized topical and transdermal formulations, highlighting the specific formulations that enhance active substance delivery while minimizing skin irritation potential.