The residual limb of transtibial amputation (TTA) prosthetic users is threatened daily by pressure ulcers (PU) and deep tissue injury (DTI) caused mainly by sustained mechanical strains and stresses. Several risk factors dominate the extent of internal tissue loads in the residuum. In this study, we developed a set of three-dimensional finite element (FE) models that were variants of a patient-specific FE model, built from magnetic resonance imaging scans. The set of FE modes was utilized to assess the impact of the following risk factors on the strain/stress distribution in the muscle flap: (i) the tibial length, (ii) the tibial bevelment, (iii) a fibular osteophyte, (iv) the mechanical properties of the muscle, and (v) scarring in different locations and depths. A total of 12 nonlinear FE model configurations, representing variations in these factors, were built and solved. We present herein calculations of compression, tension and shear strains and stresses, von Mises stresses, and strain energy density averaged in critical locations in the muscle flap as well as volumes of concentration of elevated stresses in these areas. Our results overall show higher stresses accumulating in the bone proximity rather than in outlying soft tissues. The longer bone configurations spread the loads toward the external surfaces of the muscle flap. When shortening the truncated bones from 11.2 to 9.2 cm, the von Mises stresses at the distal edges of the bones were relieved considerably (by up to 80%), which indicates a predicted decreased risk for DTI. Decreasing the tibial bevelment mildly, from 52.3 degrees to 37.7 degrees caused propagation of internal stresses from the bone proximity toward the more superficial soft tissues of the residuum, thereby also theoretically reducing the risk for DTI. An osteophyte at the distal fibular end increased the strain and stress distributions directly under the fibula but had little effect (<1%) on stresses at other sites, e.g., under the tibia. Elevation of muscle stiffness (instantaneous shear modulus increase from 8.5 to 16.2 kPa), simulating variation between patients, and muscle flap contraction or spasm, showed the most substantial effect by an acute rise of the von Mises stresses at the bone proximity. The mean von Mises stresses at the bone proximity were approximately twofold higher in the contracted/spastic muscle when compared to the flaccid muscle. Locating a surgical scar in different sites and depths of the residuum had the least influence on the overall loading of the muscle flap (where stresses changed by <7%). Pending further validation by epidemiological PU and DTI risk factor studies, the conclusions of this study can be incorporated as guidelines for TTA surgeons, physical therapists, prosthetists, and the TTA patients themselves to minimize the onset of PU and DTI in this population. Additionally, the present analyses can be used to guide or focus epidemiological research of PU and DTI risk factors in the TTA population.