Stress is an uncontrolled psychological or emotional condition that disturbs cellular homeostasis [
1]. Among the many types of tissues in the body, the brain is more susceptible to stress because of its high levels of intracellular mediators that are involved in the stress response (glucocorticoid receptors) [
2]. Stress may induce a variety of central nervous system abnormalities, including depression, anxiety, locomotor activity, and cognitive function [
3]. The main mechanism(s) associated with stress-induced behavioral disorders is the activation of the hypothalamo-hypophyseal-adrenal (HPA) axis, which involves elevation of the brain corticosterone level [
4]. The increased level of corticosterone results in a rapid depolarization that evoked glutamate release in the cortical and limbic regions [
5]. The over-production of glutamate can lead to a mitochondrial dysfunction and an increase in metabolic rate [
6]. The increased metabolic rate produces extra free radicals, leading to an imbalance between reactive oxygen species (ROS) generation and anti-oxidant system [
7]. These free radical species result in oxidative damage to different molecules in cells, such as proteins, lipids, and nucleic acids [
7]. Brain is especially sensitive to oxidative stress due to its high content of readily oxidizable fatty acids, high consumption of oxygen, and low levels of antioxidants. The increased ROS and also lowered levels of antioxidants have been associated with the pathogenesis of neurodegenerative diseases such as depression and cognitive impairment [
8]. However, the enhancement of antioxidant system may be effective to combat against the excessive ROS production [
9‐
11]. According to strong evidences, the several natural antioxidants may be effective against stress-induced mental health complications [
12]. Carnosol (CS) is a natural polyphenol (dietary diterpene) seen in plants belonging to Lamiaceae family (Mint Family) such as sage, rosemary, lavenders, and oregano [
13]. Studies indicated that CS has many pharmacological effects, including antioxidant, anti-inflammatory, anti-microbial, and anti-cancer activities [
14,
15]. The antioxidant activity of CS is activated via the catechol hydroxyl and is changed to a carnosol quinine. This quinone derivative is the main antioxidant products of CS, and has very weak antioxidant activity, but, under proper conditions the antioxidant activity can be ameliorated [
14]. Previous studies indicated that culinary herbs such as rosemary may be effective for treating the neurodegenerative disorders in animal models. Recently, it was observed that the hydroalcoholic crude extract of
R. officinalis as well as essential oil, the isolated compounds CS and betulinic acid caused an antidepressant-like effect in mice by evaluating the forced swimming test (FST) and tail suspension test (TST), that are the predictive tests of antidepressant activity, through a mechanism dependent on the interaction with the monoaminergic systems [
16]. However, the involvement of this effect on brain and its anti−/pro-oxidative aspect has not yet been studied. Considering the protective effect of CS on the function of free radicals, the study was designed to investigate the protective effect of CS on the behavioral changes in the FST, open field test (OFT) and hippocampal antioxidant imbalance induced by the chronic restraint stress. We chose the antidepressant, fluoxetine, as a positive control in our experiment.