Significant evidence from epidemiological investigations showed that dietary polyphenols might manage and prevent type 2 diabetes (T2D). This review summarizes human studies and clinical trials of polyphenols as anti-diabetic agents. Polyphenols from coffee, guava tea, whortleberry, olive oil, propolis, chocolate, red wine, grape seed, and cocoa have been reported to show anti-diabetic effects in T2D patients through increasing glucose metabolism, improving vascular function as well as reducing insulin resistance and HbA1c level. However, individual flavonoid or isoflavonoid compounds appear to have no therapeutic effect on diabetes, based on the limited clinical data. Preliminary clinical trials provided evidence that resveratrol had anti-diabetic activity in humans by improving glycemic control in subjects with insulin resistance. Besides, anthocyanins exhibited anti-diabetic properties by reducing blood glucose and HbA1c levels or the improvement of insulin secretion and resistance. The structure-activity relationship of polyphenols as anti-diabetic agents in humans has been rarely reported.