Background: Caregivers represent the core of patients’ care in hospital structures, in the process of care and self-care after discharge. We aim to identify the factors that affect the strain of caring for orthopedic patients and how these factors are related to the quality of life of caregivers. We also want to evaluate the role of caregivers in orthopedic disease, focusing attention on the patient–caregiver dyad. Methods: A comprehensive search on PubMed, Cochrane, CINAHL and Embase databases was conducted. This review was reported following PRISMA statement guidance. Studies were selected, according to inclusion and exclusion criteria, about patient–caregiver dyads. For quality assessment, we used the MINORS and the Cochrane Risk of BIAS assessment tool. Results: 28 studies were included in the systematic review; in these studies, 3034 dyads were analyzed. Caregivers were not always able to bear the difficulties of care. An improvement in strain was observed after behavioral interventions from health-care team members; Conclusions: The role of the caregiver can lead to a deterioration of physical, cognitive and mental conditions. The use of behavioral interventions increased quality of life, reducing the strain in caregivers of orthopedic patients. For this reason, it is important to consider the impact that orthopedic disease has on the strain of the caregiver and to address this topic.