Orthropaedic clinical practice in the area of the knee, hip, and spine has benefited from the concept of regional interdependence, where interventions applied to one region can influence the outcome and function of other regions of the body that may be seemingly unrelated to the applied intervention. An understanding of the biomechanical mechanisms that describe clinical practice involving knee, hip, and spine regional interdependence can improve treatment of a wide range of pathological conditions. Improvement in this area can be particularly impactful on the outcomes of patients with total joint replacement, where pathology and compensatory strategies develop during multi-joint interactions. Additionally, probabilistic methods are well suited to address knee, hip, and spine regional interdependence by using input distributions to quantify the impact of variability on the range of possible output variables. Outputs from probabilistic methods include variable interaction effects and provides sensitivity information, resulting in a more comprehensive evaluation of a system The main objectives of the work presented in this dissertation were to further our understanding of the interdependencies of the knee, hip, and spine with probabilistic musculoskeletal modeling. These objectives were achieved by developing a probabilistic plugin for use in OpenSim and performing investigations of the regional interdependence of the knee, hip, and spine involving patients with total joint replacement. An initial study identified how uncertainty in musculoskeletal simulation inputs can propagate through the stages of analysis and impact interpretation of outputs from a simulation of gait. Second, improvements to current modeling methodology for patients with total hip arthroplasty were made through the implementation of patient-specific strength scaling and input uncertainty assessment. The third study then applied these methods in an investigation of knee, hip, and spine regional interdependence in rehabilitation of patients with total hip arthroplasty to quantify the influence of simulated strengthening of hip musculature on the dynamic and mechanical interdependencies of the knee, hip and spine. A final study demonstrated how population-based musculoskeletal modeling can further impact the study of knee, hip, and spine regional interdependence by presenting the feasibility study of performing population-based musculoskeletal modeling. These studies include several novel methods for investigating the regional interdependencies of the knee, hip, and spine that have been used to translate outputs from musculoskeletal simulations into rehabilitation practice.