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Rats were administered <jats:italic>O.\u2009sanctum<\/jats:italic> followed by CVS regimen for a period of 16\u2009days. On days 4, 8, 12, and 16, body weight and immobility time in forced swim test were measured. In addition, the possible inhibitory effect of <jats:italic>O.\u2009sanctum<\/jats:italic> and ursolic acid on cortisol release and CRHR1 receptor activity were studied in cell\u2010based assays, while inhibitory effects on 11\u03b2\u2010hydroxysteroid dehydrogenase type 1 (11\u03b2\u2010HSD1) and catechol\u2010<jats:italic>O<\/jats:italic>\u2010methyltransferase (COMT) were studied in cell\u2010free assays. CVS group demonstrated less body weight gain and higher immobility time than <jats:italic>O.\u2009sanctum<\/jats:italic> administered groups, while oral administration of <jats:italic>O.\u2009sanctum<\/jats:italic> significantly increased body weight gain and decreased the immobility time. Further, <jats:italic>O.\u2009sanctum<\/jats:italic> and its constituents inhibited cortisol release and exhibited a significant CRHR1 receptor antagonist activity. Also, they had specific inhibitory activity towards 11\u03b2\u2010HSD1 and COMT activity. Thus, <jats:italic>O.\u2009sanctum<\/jats:italic> was found to be effective in the management of stress effects, and anti\u2010stress activity could be due to inhibition of cortisol release, blocking CRHR1 receptor, and inhibiting 11\u03b2\u2010HSD1 and COMT activities. 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