Existing reviews exploring cannabis effectiveness have numerous limitations including narrow search strategies. We systematically explored cannabis effects on PTSD symptoms, quality of life (QOL), and return to work (RTW). We also investigated harm outcomes such as adverse effects and dropouts due to adverse effects, inefficacy, and all-cause dropout rates. Our search in MEDLINE, EMBASE, PsycInfo, CINAHL, Web of Science, CENTRAL, and PubMed databases, yielded 1 eligible RCT and 10 observational studies (n = 4672). Risk of bias (RoB) was assessed with the Cochrane risk of bias tool and ROBINS-I. Evidence from the included studies was mainly based on non-randomized studies with no comparators. Results from unpooled, high RoB studies showed that cannabis was associated with a reduction in overall PTSD symptoms and improved QOL. Dry mouth, headaches, and psychoactive effects such as agitation and euphoria were the commonly reported adverse effects. In most studies, cannabis was well tolerated, but small proportions of patients experienced a worsening of PTSD symptoms. Evidence in the current study primarily stems from low quality and high RoB observational studies. Further RCTs investigating cannabis effects on PTSD treatment should be conducted with larger sample sizes and explore a broader range of patient-important outcomes. © 2021 the Author(s), licensee AIMS Press.