Objective: To investigate the cardioprotective effect of Saffron (Crocus sativus L.) treatment as a potential supplement on patients with type 2 diabetes mellitus (T2DM). Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied to analyze articles retrieved from PubMed, ScienceDirect, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), and China Biology Medicine (CBM) with a publication time span from January 15, 2015 to March 20, 2023. The articles were published in English only, including randomized controlled trials (RCTs) on adult patients who were diagnosed with T2DM, and received either Saffron or placebo treatment. Meta-analysis was performed using Review Manager 5.4 software. The present study was registered on the International Prospective Register of Systematic Reviews (PROSPERO) with a registration number as CRD42023443180. Results: Seven RCTs with 455 patients were included in the study. The data revealed that Saffron treatment significantly reduced tumor necrosis factor (TNF)-α (P = 0.008) and fasting blood glucose (FBG) (P = 0.04) levels compared with what placebo did in T2DM patients. No significant differences were shown in the levels of interleukin (IL)-6, malondialdehyde (MDA), high serum C-reactive protein (hs-CRP), lipid profile, blood pressure, and body mass index (BMI) between Saffron and placebo ( P > 0.05) . Conclusion Saffron treatment has a cardioprotective effect in T2DM patients by reducing TNF-α and FBG levels. However, the potential anti-oxidant, anti-hypertensive, and anti-dyslipidaemia effects of the phytochemical need to be further investigated.