The aim of this study was to systematically review the literature to identify factors that may influence quality of life in people with lower-limb amputation (all etiologies). Our primary focus was on identifying factors that can be modified, enabling a more concentrated integration of these aspects into the care and treatment of amputated patients. Medline (via Ovid) and Scopus were searched in January 2023 for studies assessing quality of life for people with lower-limb loss. Studies were included if they reported on factors that could influence quality of life. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies were identified and assessed independently by 2 reviewers. Data were extracted by 2 independent reviewers. After removing duplicates, the search yielded 2616 studies, of which 24 met our inclusion criteria (cross-sectional n = 13; prospective n = 9; retrospective n = 2). The most commonly used quality-of-life instruments were the Short Form 36, followed by the World Health Organization Quality of Life-BREF and the EuroQoL 5 dimension. Younger age, traumatic etiology, unilateral or below-knee amputation, presence of comorbidities, and social integration were found to influence quality of life in people with lower-limb amputation, whereas sex and socioeconomic context do not seem to have a clear influence. This systematic review of the literature identified several factors that influence quality of life in patients with lower-limb amputation. However, the results are not always consistent across studies and there is still no consensus on some factors. Conclusive findings regarding sex and socioeconomic status remain elusive, primarily because of substantial disparities observed across the literature. Future prospective longitudinal studies with clear a priori inclusion of a wide range of potential factors are needed to clarify the impact of the identified factors. Factors such as age, type of amputation, comorbidities and social integration should be considered in the management of patients with amputation.