There is a growing importance for environmental contributions to psychiatric disorders and understanding the impact of the exposome (i.e., pollutants and toxins). Increased biomonitoring and epidemiological studies, for example, suggest that daily phthalate chemical exposure contribute to neurological and behavioral abnormalities, however these mechanisms remain poorly understood. The current study therefore aimed to examine the effects of chronic phthalate exposure on rodent anxiety behaviors, cognition, and the impact on hypothalamic-pituitary- adrenal (HPA)-axis function. Adult male mice (C57BL6/J) were administered mono-2-ethylhexyl phthalate (MEHP) via drinking water (1 mg/ml), and anxiety-like behavior, cognition combined with HPA- axis and inflammatory assays were assessed after 3 weeks of MEHP exposure. MEHP-treated mice exhibited enhanced generalized anxiety-like behaviors, as demonstrated by reduced time spent in the open-arm of the elevated plus maze (EPM) and center exploration in the open field (OF). Tests of spatial, cognition and memory function were unchanged. Following MEHP administration, circulating levels of corticosterone and pro- inflammatory cytokines were significantly increased, while at the tissue level, MEHP-dependent reductions in glucocorticoid metabolism genes 11β-hydroxysteroid dehydrogenase (11β-HSD) 1 and 2. These data suggest that chronic MEHP exposure leads to enhanced generalized-anxiety behaviors independent of rodent measures of cognition and memory, which maybe driven by MEHP-dependent effects on HPA-axis and peripheral glucocorticoid metabolism function.