Objective: This systematic review aims to investigate Quality of Life (QoL)/Health Related Quality of Life (HRQoL) and psychological adjustment in non-traumatic lower limb amputees (LLA). Methods: PubMed, Scopus, and Web of Science databases were used for the literature search. Studies were read and analysed using the (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) PRISMA statement procedure. Results: The literature search retrieved 1268 studies, of which 52 were included in the systematic review. Overall, psychological adjustment, especially depression with or without anxiety symptoms, influences the QoL/HRQoL in this clinical population. Other factors influencing QoL/HRQoL include subjective characteristics, physical aspects, the cause and level of the amputation, relational aspects, social support, and the doctor-patient relationship. In addition, the patient’s emotional-motivational status, depression and/or anxiety symptoms, and acceptance play a key role in the subsequent rehabilitation process. Conclusions: In LLA patients, psychological adjustment is a complex and multifaceted process, and QoL/HRQoL may be influenced by various factors. Shedding light on these issues may provide useful suggestions for promoting clinical and rehabilitative interventions that may be tailored and effective in this clinical population.