Polyphenols, a category of plant compounds that contain multiple phenol structural units, are widely distributed throughout the plant kingdom and have multiple benefits for human health including anti-obesity, anti-hyperglycemic, and anti-hyperlipidemic effects. Additionally, polyphenols have recently gained attention for their anti-stress effects. In this review article, we summarize physiological responses against exposure to stressors and discuss biomarkers for exposure to stressors that are widely used in animal studies and human trials. We also review commonly used animal models for evaluating anti-stress effects. Finally, we discuss recent findings related to the anti-stress effects of polyphenols evaluated in animal models and human trials, and their putative mechanisms. These emerging data require further investigation in scientific studies and human trials to evaluate the anti-stress effects of polyphenols and their potential use for the prevention of stress-related health problems.