Physical exercise seems to have a promising effect on numerous variables related to the recovery of drug-dependent patients. However, some contradictions are found in the literature. The aim of this study was to perform a systematic review and meta-analysis in order to identify the effect of physical exercise on mental disorders, quality of life, abstinence, and craving, and make a comparison of the effect of exercise depending on the type of program. A search for articles was conducted using PubMed, Web of Science, and Scopus databases. Studies were selected that measured the acute effects or long-term effect (≥2 weeks) of exercise in patients who met criteria for alcohol use disorders or substance use disorders. A total of 59 studies were included. An effect of exercise on mental disorders (standardized mean differences (SMD) = 0.66 (confidence interval (CI): 0.46, 0.86); z = 6.50; p < 0.00001) and quality of life (SMD = 0.69 (95% CI: 0.53, 0.84); z = 8.65; p < 0.00001) was identified. Subgroup analysis revealed an effect of exercise in craving (SMD = 0.80 (CI: 0.07, 1.53); z = 2.15, p = 0.03), stress (SMD = 1.11 (CI: 0.31, 1.91); = 2.73; p = 0.006), anxiety (SMD = 0.50 (CI: 0.16, 0.84); z = 2.88; p = 0.004) and depression (SMD = 0.63 (CI: 0.34, 0.92); z = 4.31; p < 0.0001). Body–mind activities and programs based on improving physical conditions produced similar results in mental disorders and quality of life. Available evidence indicates that physical exercise, both body–mind and physical fitness programs, can be effective in improving mental disorders, craving, and quality of life in drug-dependent patients. Keywords: substance use disorders, drug addiction, physical exercise, physical activity, quality of life, mental disorders, anxiety, depression, stress, craving