Donor site morbidity remains a significant concern in free flap microsurgery, with implications that extend beyond immediate postoperative outcomes to affect patients’ long-term quality of life. This review explores the multi-faceted impact of donor site morbidity on physical, psychological, social, and occupational well-being, synthesizing findings from the existing literature. Particular attention is given to the functional limitations, sensory deficits, aesthetic outcomes, and chronic pain associated with commonly utilized free flaps. Advancements in surgical techniques, including nerve-sparing and muscle-sparing methods, as well as innovations, like perforator flaps, have demonstrated the potential to mitigate these morbidities. Furthermore, the integration of regenerative medicine strategies, such as stem cell therapy and fat grafting, and technological innovations, including virtual reality rehabilitation and biofeedback devices, has shown promise in enhancing recovery and minimizing long-term complications. Despite these advances, challenges persist in standardizing QoL assessments and optimizing donor site management. This review emphasizes the need for a holistic, patient-centered approach in reconstructive microsurgery, advocating for further research to refine current strategies, improve long-term outcomes, and develop robust tools for QoL evaluation. By addressing these gaps, reconstructive surgeons can better align surgical objectives with the comprehensive well-being of their patients.