Psychiatric morbidity commonly coexists with substance abuse and HIV/AIDS around the globe. This review study aimed to determine the available literature on the prevalence of common substance abuse/use and common mental health illnesses among HIV/AIDS patients worldwide to help policymakers design appropriate strategies to limit extensive substance use and prevent common mental and health illnesses. For the comprehensive literature review, Google Scholar, PubMed Central, Medline, and PakMediNet biomedical databases were searched for original and reviewed studies published in English, from January 2000 to September 2021. Selections of studies and extraction of data from the studies were performed based on quality and inclusion criteria. MedCalc Meta-analysis Software Package version 20.009 was used for data analysis. Out of 103,024 HIV/AIDS patients inspected in 30 studies, 6430 HIV/AIDS patients had pooled prevalence of depression 30.31% (95%CI: 26.028 to 34.786), and 6927 study participants reported the overall current pooled prevalence of any substance use was 25.13% (95%CI: 11.526 to 41.897), respectively. Current alcohol consumption and tobacco smoking are the most common substance abuse, and depression and anxiety are the most common mental health disorders among HIV/AIDS patients. There was no significant publication bias, but substantial heterogeneity was observed in the presented studies. The current systematic review and meta-analysis showed a greater prevalence of substance abuse and mental health illnesses among HIV/AIDS patients than the general population at the global level. Key Words: Substances, Substance use, Substance abuse, Alcohol abuse, Tobacco smoking, HIV/AIDS, Depression, Anxiety, Mental health, HIV/AIDS, Worldwide.