Abstract Background Crocin as a carotenoid exerts anti-oxidant, anti-inflammatory, anti-cancer, neuroprotective and cardioprotective effects. Besides, the increasing prevalence of diabetes mellitus and its allied complications, and also patients' desire to use natural products for treating their diseases, led to the design of this study to evaluate the efficacy of crocin on glycemic control, insulin resistance and active adenosine monophosphate-activated protein kinase (AMPK) levels in patients with type-2 diabetes (T2D). Methods In this clinical trial with a parallel-group design, 50 patients with T2D received either 15-mg crocin or placebo, twice daily, for 12 weeks. Anthropometric measurements, dietary intake, physical activity, blood pressure, glucose homeostasis parameters, active form of AMPK were assessed at the beginning and at the end of the study. Results Compared with the placebo group, crocin improved fasting glucose level (P = 0.015), hemoglobin A1c (P = 0.045), plasma insulin level (P = 0.046), insulin resistance (P = 0.001), and insulin sensitivity (P = 0.001). Based on the within group analysis, crocin led to significant improvement in plasma levels of glucose, insulin, hemoglobin A1c, systolic blood pressure, insulin resistance and insulin sensitivity. The active form of AMPK did not change within and between groups after intervention. Conclusions The findings indicate that crocin supplementation can improve glycemic control and insulin resistance in patients with T2D. Further studies are needed to confirm these findings. Trial Registration This study has been registered at Clinicaltrial.gov with registration number NCT04163757