This work was divided into three study phases: the two-phase randomized controlled clinical trials and proteomics study. First, the phase I clinical trial aimed to determine efficacy and safety of mulberry leaves on postprandial glucose following the 50-g sucrose ingestion in healthy nondiabetic adults and to explore the optimal administered dose of 1-deoxynojirimycin (DNJ), the major antihyperglycemic compound of mulberry leaves. The results showed the alleviation of postprandial hyperglycemia by mulberry leaves in a dose-dependent fashion. Adverse effects of mulberry leaves included bloating and flatulence, loose stool, and nausea. In addition, 12 mg of DNJ was considered the optimal dose defined by the clinically effective dose with the minimal side effects. Second, the phase II clinical trial was conducted to determine efficacy and safety of the long-term administration of mulberry leaves on glycemic control in patients with obesity and patients with type 2 diabetes. Daily administration of mulberry leaves containing 12 mg of DNJ thrice daily before meals resulted in the improvement in glycemic control as well as insulin sensitivity in the mulberry leaves-treated group; however, there was no difference between the treatment group and the control. Moreover, mulberry leaves were capable of reducing blood lipids when compared with the control group. Our study did not observe the changes in hepatic and renal function by mulberry leaves administration. Nonetheless, it caused bloating and flatulence, loose stool, and constipation. Last, effects of mulberry leaves on expressions of plasma proteins of persons who enrolled the phase II clinical study were further determined using proteomics analysis. In response to mulberry leaves treatment, the analysis found modulation in expressions of proteins involved in metabolic regulation, extracellular matrix constituents and organization, immunity, and inflammatory response.