Nowadays, additive manufacturing (AM) via the Fused Filament Fabrication (FFF) 3D printing process offers promising opportunities for the customized manufacturing of ankle–foot orthoses based on polypropylene (PP). However, optimizing printing parameters remains a major challenge due to the specific properties of this polyolefin, particularly its low interlayer adhesion and volumetric shrinkage. The primary innovation of the present work lies in the optimization of printing conditions for the production of patient-specific orthoses using PP, a material still underutilized in the AM of biomedical devices. Firstly, a thorough thermo-mechanical characterization was conducted, allowing the implementation of a (thermo-)elastic material model for the used PP filament in the simulation software database (Digimat-AM®). Thereafter, a Taguchi design of experiments was established to study the influence of several printing parameters (extrusion temperature, layer thickness, infill density, infill pattern and part orientation) on the mechanical properties of 3D printed specimens. Three-point bending tests were conducted to evaluate the strength and stiffness of the samples, while additional tensile tests were performed on the 3D printed orthoses according to ISO 22675 standard to validate the optimal configurations. Finally, the applicability of the finite element method (FEM) to simulate the FFF process-induced deflections, part distortion (warpage) and residual stresses in 3D printed orthoses was investigated using Digimat-AM® numerical simulation tool. The comparison between experimental results and numerical simulations enabled the proposal of an optimized set of parameters, ensuring improved quality and robustness of the printed orthoses. The findings of this study contribute to a better understanding of ankle–foot orthosis 3D printing with polypropylene, paving the way for more reliable and customized production targeted towards rehabilitation purposes.