Stress plays a major role in various pathophysiological processes related with neurodegenerative diseases and mental disorders. Zebrafish has emerged as a promising model organism in inducing Chronic Unpredictable Stress (CUS). In the present study, we have attempted to understand the molecular basis of neuronal changes underlying CUS in zebrafish model. An evidence for a connection between CUS and apoptosis in the brain of zebrafish was analyzed. For this purpose, zebrafish were subjected to CUS protocol twice a day for a period of 15 days. The impact of CUS on the brain was evaluated in relation to the expression of the stress marker genes: corticotropin releasing factor (crf) and glucocorticoid receptor (gr). The effects of CUS were also estimated from the expression of p53 mediated apoptotic genes: p53, noxa, bcl2 and casp3. CUS protocol increased the gene expression of crf (p<0.05) and decreased the expression of gr (p<0.05). The impact of CUS on the apoptotic pathway showed increased expression of p53 (p< 0.05) and noxa (p<0.05) with a decrease in expression of mitochondrial bcl2 (p<0.05). As a hallmark of apoptosis, CUS increased the expression of casp3 (p<0.05). In principle, CUS has the potency to exert their detrimental effects on the neuronal cells of the brain and has confirmed p53 induced apoptosis in the brain of zebrafish.