BACKGROUND: Despite several studies about the effects of saffron supplementation on serum concentrations of lipid and glucose profiles, no systematic study had summarized the findings. Therefore, we conduct current study to systematically summarize findings from studies about the effect of saffron supplementation on serum levels of glucose and lipid profiles and to do a meta-analysis, if possible. METHODS: A systematic literature search was conducted for clinical trials published in PubMed, SCOPUS, EMBASE, Cochrane's Library and ISI Web of Science from the beginning to 22 February 2019. All randomized clinical trials on the effect of saffron supplementation on serum concentrations of lipid and glucose profiles were included. RESULTS: In overall, six studies were included in the current study. Pooled analysis of six studies for the effect of saffron on serum TG, TC and FBG concentrations and of five studies for LDL and HDL, showed a significant reduction in TG (WMD: -8.93 mg/dl; 95% CI: -16.49 to -1.37, P = 0.02) and TC levels (WMD: -5.72 mg/dl; 95% CI: -11.10 to -0.34, P = 0.03), a significant increase in HDL levels (WMD: 2.7 mg/dl; 95% CI: 0.22 to 5.18, P = 0.03), and no significant effect on LDL (WMD: -2.30 mg/dl; 95% CI: -11.73 to 7.13, P = 0.63) and FBG levels (WMD: -5.30 mg/dl; 95% CI: -14.20 to 3.60, P = 0.51). CONCLUSION: We found a significant reduction in serum concentrations of TC and TG and a significant increase in serum levels of HDL following supplementation with saffron. Saffron supplementation had no significant influence on serum FPG and LDL concentrations.