Deep tissue injury (DTI) is a potentially life-threatening form of pressure ulcer that onsets in muscle tissue overlying bony prominences and progresses unnoticeably to more superficial tissues. To minimize DTI, the efficacy of wheelchair cushions should be evaluated not only based on their performance in redistributing interface pressures but also according to their effects on stress concentrations in deep tissues, particularly muscles. However, a standard bioengineering approach for such analyses is missing in literature. The goals of this study were to develop an algorithm to couple finite element (FE) modeling of the buttocks with an injury threshold for skeletal muscle and with a damage-stiffening law for injured muscle tissue, from previous animal experiments, to predict DTI onset and progression for different patient anatomies and wheelchair cushions. The algorithm was also employed for identifying intrinsic (anatomical) biomechanical risk factors for DTI onset. A set of three-dimensional FE models of seated human buttocks was developed, representing different severities of pathoanatomical changes observed in chronically sitting patients: muscle atrophy and “flattening” of the ischial tuberosity (IT). These models were then tested with cushions of different stiffnesses representing products available on the market and semirigid supports. Outcome measures were the percentage of damaged muscle tissue volumes after and of simulated continuous immobilized sitting as well as muscle injury rates post-, -, and - of continuous sitting. Damaged muscle volumes grew exponentially with the level of muscle atrophy. For example, simulation of a subject with 70% muscle atrophy sitting on a soft cushion showed damage to 33% of the muscle volume after of immobilized sitting, whereas a comparable simulation with a nonatrophied muscle yielded only 0.4% damaged tissue volume. The rates of DTI progression also increased substantially with increasing severities of muscle atrophy, e.g., 70% atrophy resulted in 8.9, 2.7, and 1.6 times greater injury rates compared with the “reference” muscle thickness cases, after , , and of sitting, respectively. Across all simulation cases, muscle injury rate was higher when a “flatter” IT was simulated. Stiffer cushions increased both the extent and rate of DTI at times shorter than of continuous sitting, but after , volumes and rates of tissue damage converged to approximately similar values across the different cushion materials. The present methodology is a practical tool for evaluating the performances of cushions in reducing the risk for DTI in a manner that goes far beyond the commonly accepted measurements of sitting pressures.