Stress is a psychological and physiological state that leads to release of cortisol from the adrenal gland, and is associated with several complications if left untreated. This review was conducted to investigate the effects and action mechanisms of medicinal plants and their derivatives on cortisol. To conduct this systematic review, the key words of interest were used to retrieve relevant articles from databases the Information Sciences Institute and PubMed. Then, the plants and the plant-based products that were effective in corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol and therefore control stress, were selected. According to the inclusion and exclusion criteria, the results of 19 articles were analyzed. The plants and their derivatives help regulate the key mediators and cytokines effective in stress response via targeting the hypothalamicpituitary-adrenal (HPA) axis. In addition, they can induce anti-stress properties via changing and modulating oxidative and nitrosative stress biomarkers. Regulation of certain stress hormones receptors and corticotropin releasing factor is another mechanism of the plants and their derivatives in reducing stress. The plants and their derivatives have exhibited their therapeutic effects on mild stress and they are also effective in treating more severe disorders such as chronic stress through affecting the HPA. They can be considered an independent or supplementary treatment alongside chemotherapies to decrease cortisol levels and to induce calmness.