Large or carcinogenic bone defects may require a challenging bone tissue scaffold design ensuring a proper mechanobiological setting. Porosity and biodegradation rate are the key parameters controlling the bone-remodeling process. PLA presents a great potential for geometrically flexible 3-D scaffold design. This study aims to investigate the mechanical variation throughout the biodegradation process for lattice-type PLA scaffolds using both experimental observations and simulations. Three different unit-cell geometries are used for creating the scaffolds: basic cube (BC), body-centered structure (BCS), and body-centered cube (BCC). Three different porosity ratios, 50 %, 62.5 %, and 75 %, are assigned to all three structures by altering their strut dimensions. 3-D printed scaffolds are soaked in PBS solution at 37 °C for 15, 30, 60, 90, and 120 days both unloaded and under dead load. Water absorption, weight loss, and compression stiffness are measured to characterize the first-stage degradation and investigate the possible influences of these parameters on the whole biodegradation process. The strength reduction stage of biodegradation is simulated by solving pseudo-first-order kinetics-based molecular weight change equation using FEA with equisized cubic (voxel-like) elements.For the first stage, mechanical load does not have a statistically significant effect on biodegradation. BCC with 62.5 % porosity shows a maximum water absorption rate of around 25 % by the 60th day which brings an advantage in creating an aquatic environment for cell growth. Results indicate a significant water deposition inside almost all scaffolds and water content is determined to be the main reason for the retained or increased compression stiffness. A distinguishable stiffness increase in the initial degradation process occurs for 75 % porous BC and 50 % porous BCC scaffolds. Following the quasi-stable stage of biodegradation, almost all scaffolds lost their rigidity by around 44–48 % within 120 days based on numerical results. Therefore, initial stiffness increase in the quasi-stable stage of biodegradation can be advantageous and BCC geometry with a porosity between 50% and 62 % is the optimum solution for the whole biodegradation process.