It has been recognized that the cross-sectional curvatures of lower extremities directly influence pressure magnitudes and distributions exerted by compression garments. In the practice of compression therapy, higher peak pressures produced by compression shells occurred at anatomic sites with smaller radius of curvatures and led to side effects and discomfort perception. An effective and operational method to determine leg curvature properties in order to predict pressure performances is desirable to improve comfort and mechanical function of compression garment. By employing three-dimensional (3D) digital anthropometry and two-dimensional (2D) digital image simulation, the curvatures and radius of curvatures of a total of 300 cross-sectional slices involving 1200 anatomic sites along the lower limbs were determined onto the ten healthy female subjects when they were and were not wearing compression stockings. Based on the determined cross-sectional characteristics, the skin pressures were calculated using the circumference-based and the radius of curvature-based Laplace’s equations, respectively, which were further validated against the experimental skin pressures measured by a PicoPress transducer. This study provided quantitative evidence in the exploration of the working mechanisms of uneven pressures produced by compression garments, and established a standardized method to determine cross-section-related curvature characteristics for pressure assessment and prediction, which will contribute to improving user compliance of compression garments in long-term wear.