Psychological stress (PS) increases endogenous glucocorticoids (GC) by activating the hypothalamic-pituitary-adrenal axis. The negative effects of GC on skin barrier function under PS have been well-established. However, endogenous GC can also be active when cortisone (inactive form) is converted to cortisol (active form) by 11β-hydroxysteroid dehydrogenase type I (11ß-HSD1) in the peripheral tissue. Here, we evaluated the changes in 11ß-HSD1 and barrier function under PS. Elevated 11ß-HSD1 in oral mucosa correlated with increased cortisol in the stratum corneum and deteriorated barrier function. Expression of 11ß-HSD1 in the oral mucosa correlated with that in the epidermal keratinocytes. We further investigated whether barrier function improved when PS was relieved using a selective serotonin reuptake inhibitor (SSRI) in patients with anxiety. Decreased 11ß-HSD1 and improved barrier function were observed after SSRI treatment. The collective findings suggest that elevated 11ß-HSD1 under PS increases the level of cutaneous GC and eventually impairs barrier function. PS-alleviating drugs, such as SSRI, may help to treat PS-aggravated skin diseases.