Stress plays a key role in mental, neurological, endocrine, and immune disorders. The zebrafish (Danio rerio) is rapidly gaining popularity as s model organism in stress physiology and neuroscience research. Although the leopard (leo) fish are a common outbred zebrafish strain, their behavioral phenotypes and stress responses remain poorly characterized. Here, we examined the effects of a 5-week chronic unpredictable stress (CUS) exposure on adult leo zebrafish behavior, cortisol levels, and brain gene expression. Compared to their unstressed control leo counterparts, CUS-exposed fish showed paradoxically lower anxiety-like, but higher whole-body cortisol levels and altered expression of multiple pro- and anti-inflammatory brain genes. Taken together, these findings suggest that behavioral and physiological (endocrine and genomic) responses to CUS do differ across zebrafish strains. These findings add further complexity to systemic effects of chronic stress in vivo and also underscore the importance of considering the genetic background of zebrafish in stress research.