Multiply injured patients with severe extremity trauma are at risk of acute systemic complications and are at high risk of developing longer term orthopaedic complications including soft-tissue infection, osteomyelitis, posttraumatic osteoarthritis, and nonunion. It is becoming increasingly recognized that injury magnitude and response to injury have major jurisdiction pertaining to patient outcomes and complications. The complexities of injury and injury response that affect outcomes present opportunities to apply precision approaches to understand and quantify injury magnitude and injury response on a patient-specific basis. Here, we present novel approaches to measure injury magnitude by adopting methods that quantify both mechanical and ischemic tissue injury specific to each patient. We also present evolving computational approaches that have provided new insight into the complexities of inflammation and immunologic response to injury specific to each patient. These precision approaches are on the forefront of understanding how to stratify individualized injury and injury response in an effort to optimize titrated orthopaedic surgical interventions, which invariably involve most of the multiply injured patients. Finally, we present novel methods directed at mangled limbs with severe soft-tissue injury that comprise severely injured patients. Specifically, methods being developed to treat mangled limbs with volumetric muscle loss have the potential to improve limb outcomes and also mitigate uncompensated inflammation that occurs in these patients.