Lower-extremity lymphedema (LEL) is a progressive, lifelong complication of cancer that places a substantial burden upon cancer survivors’ quality of life (QOL) and psychosocial well-being. Despite its prevalence, cancer-related LEL is inconsistently diagnosed, treated, and poorly recognized by health care professionals. The purpose of this systematic review was to summarize and appraise the quantitative literature evaluating the impact of cancer-related LEL on patients’ psychosocial well-being and QOL. Three databases (PubMed, PROQuest, and Scopus) were searched for observational research articles published before May 1st, 2020. Twenty-one articles were eligible (cross-sectional (n = 16), prospective cohort designs (n = 3), and retrospective cohort designs (n = 2)). The majority of studies reported a negative relationship between cancer-related LEL and global QOL and/or one or more psychosocial domains including (1) physical and functional; (2) psycho-emotional; (3) social, relational and financial. A greater number of LEL symptoms and higher LEL severity were associated with poorer QOL. Although the evidence to date suggests a negative relationship between cancer-related LEL and patients’ QOL and psychosocial well-being, there is a substantial need for longitudinal analyses to examine the directionality and temporality of this effect in order to inform cancer survivorship care modelling and improve patient outcomes after cancer.