Plant derivatives such as carotenoids and phytosterols enrich foods have been shown to reduce plasma triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and cholesterol concentrations. The aim of this systematic review and meta-analyses study was to investigate the effects of saffron on lipid profiles, reported in randomized controlled trials (RCTs). We performed a systematic electronic search in PubMed/MEDLINE, Cochrane, and SCOPUS to identify RCTs and screening of relevant articles references up to October 12, 2018. There were no language restrictions. We performed this systematic review and meta-analysis according to the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses guidelines. We identified and analyzed 14 eligible studies in this meta-analysis. Our study found a significant reduction in cholesterol and TG following saffron intervention (weighted mean difference [WMD]: -6.36 mg/dl, 95% confidence interval, CI, [-10.58, -2.18] and WMD: -5.37 mg/dl, 95% CI [-10.25, -0.48], respectively). There was no significant effect on weight and LDL concentration. A meta-regression analysis showed that long-term saffron intervention can increase the high-density lipoprotein (HDL) levels. In conclusions, our study findings indicate some benefits of saffron on cholesterol, HDL, and TG compared with placebo. However, we recommend the conduct of adequately powered, high-quality RCTs with short- and long-term follow-up, evaluating relevant clinical outcomes to allow for making definitive recommendations.