Background: The association of psychiatric illness with altered cytokine profile and changes in neurobehavior are well known. “Karisalai chooranam” (KSC) is a polyherbal preparation, contains equal proportion of six ingredients namely Eclipta prostrata Linn., Acalypha indica Linn., Sphaeranthus indicus Linn., Indigofera tinctoria Linn., Centella asiatica Linn., and Wedelia chinensis. Restraint stress is reported to be a model for psychological stress. It was hypothesized that KSC might protect against restraint stress-induced detrimental effects. Objectives: The objective is to evaluate the efficacy of KSC against detrimental effects of psychological stress. Materials and Methods: Male Wistar albino rats were subjected to restraint stress (6 h/day, 21 days). At the end of stress, rats were subjected to elevated plus maze (EPM) and Moris Water Maze studies. Blood was collected and examined for interleukin-6 (IL-6), IL-10 by Enzyme-Linked Immuno Sorbent Assay. Results: Restraint stress produced raise in the plasma IL-6 and decrease in the IL-10 level. Abnormalities in memory and anxiety level were seen. The effects of KSC in preventing detrimental effects on spatial recognition skill and reference memory were observed in Morris water maze analysis. In EPM trail, the anxiety developed due to restraint stress was prevented by the KSC. Conclusion: KSC was found to have action against psychological stress-induced neurobehavioral changes and stress-induced alteration in cytokines which play important roles in the development of psychological stress.