Substance Use Disorder (SUD) has become a significant public health concern and it profoundly impacts an individual's quality of life (QOL). This systematic review aimed to assess the QOL among patients with SUD, and to understand the differential impact of SUD on physical, mental, social, and environmental QOL domains, considering a variety of substances and identifying key factors that influence these outcomes. A comprehensive search was conducted in PubMed, Web of Science, Cochrane, and Scopus in January 2023, covering literature published until December 2022. The QOL was assessed using the World Health Organization Quality of Life (WHOQOL) instrument and the brief version of the WHOQOL, identifying the same four domains of QOL (physical, mental, social, and environmental). A total of 19 studies were selected for inclusion in the systematic review, based on individuals' polysubstance use, and excluding those using only nicotine or alcohol. The analysis included 6079 patients, with only 40.3% women, and a mean age of 36.6 years. The substances most commonly involved in SUD were cocaine (47.1%), alcohol (46.3%), and amphetamine (43.6%), considering most individuals being polysubstance users. The highest variability in QOL scores was observed in the physical domain. Mental disorders were reported in 68.3% of the patients, while long-term use of drugs, criminal history, unemployment, and low levels of education were identified as significant predictors for lower QOL by some of the studies. Similarly, sleep problems and teeth decay were also identified as significant worsening factors for QOL. This systematic review highlights that the WHOQOL survey is widely accepted and applicable for individuals with SUD worldwide. The results suggest a substantial negative impact of SUD on the QOL of affected individuals. The findings underscore the need for comprehensive interventions to address the physical, psychological, social, and environmental dimensions of QOL among individuals with SUD.