For physical-based compression therapeutic modalities, especially compression stockings (CSs), their pressure performances are necessarily evaluated by the standardized cylinder leg mannequins before biological applications. However, the insufficient pressure supply caused by morphological shape diversities between circular leg mannequins and irregular bio-bodies limits the clinical effectiveness and user compliance of CSs. Therefore, an operable and efficiency approach for optimization bio-design and digital development of CSs with enhanced compression performances needs to be proposed. The present study has adopted three-dimensional (3D) body scanning and reverse engineering technologies for lower limb cross-sectional geometric characterization and morphological classification. The irregularity of biological leg circumferential slices was determined and clustered as four levels relating to individual curvature variations. Sequentially, a new pressure prediction model was constructed through characterized geometric variations for bio-based bodies, then its acceptability was validated with good agreement by wearing trials (mean prediction accuracy was 2.53 ± 0.52 mmHg). Thus, the digital pressure reshaped development guidance was obtained based on the classified irregular levels and established pressure prediction models. Consequently, this study provides a novel reliable optimization bio-design solution for manufacturing of therapeutic compression textiles and facilitates the medical efficacy and precision of compression therapy in practical use.