The field of bone regeneration has primarily focused on investigating fracture healing and nonunion in isolated musculoskeletal injuries. Compared to isolated fractures, which frequently heal well, fractures in patients with multiple bodily injuries (polytrauma) may exhibit impaired healing. While some papers have reported the overall cytokine response to polytrauma conditions, significant gaps in our understanding remain in how fractures heal differently in polytrauma patients. We aimed to characterize fracture healing and the temporal local and systemic immune responses to polytrauma in a murine model of polytrauma composed of a femur fracture combined with isolated chest trauma. We collected serum, bone marrow from the uninjured limb, femur fracture tissue, and lung tissue over 3 weeks to study the local and systemic immune responses and cytokine expression after injury. Immune cell distribution was assessed by flow cytometry. Fracture healing was characterized using microcomputed tomography (microCT), histological staining, immunohistochemistry, mechanical testing, and small angle X-ray scattering. We detected more innate immune cells in the polytrauma group, both locally at the fracture site and systemically, compared to other groups. The percentage of B and T cells was dramatically reduced in the polytrauma group 6 h after injury and remained low throughout the study duration. Fracture healing in the polytrauma group was impaired, evidenced by the formation of a poorly mineralized and dysregulated fracture callus. Our data confirm the early, dysregulated inflammatory state in polytrauma that correlates with disorganized and impaired fracture healing.