Poly(butylene succinate) (PBS) scaffolds with 3D microporous interconnected architecture and crystallized PBS substructures have been prepared by thermally-induced phase separation (TIPS). Curcumin (CUR) and piperine (PIP) natural drugs were incorporated into the matrices during a one-step fabrication protocol. Alterations in TIPS parameters such as solvent system (1,4 dioxane (DXN) or THF) and cooling condition (intensity and direction of thermal gradient) affected the phase separation process and the scaffold properties. Controlling the crystallization of DXN in a uniaxial direction, resulted in the formation of microtubular scaffolds with oriented porosities. Well-developed PIP crystals and matrix-integrated CUR agglomerates were uniformly distributed throughout the scaffolds. The integration of CUR to the polymer matrix was confirmed by physicochemical evaluations, attributed to a possible interaction with PBS, resulting in a slower release than PIP. The scaffolds with uniaxially-oriented porosities displayed a greater sustained release (only 50–60% after 170 h) due to the restricted drug diffusion through their dense spherulitic pore walls. Due to such structure and smoother well-arranged surfaces, the oriented scaffolds also exhibited greater biocompatibility. Our results reveal the positive influence of TIPS-derived structural orientation on properties of PBS matrices for cell/drug delivery.