Elevated maternal glucocorticoid concentrations during gestation can affect how the offspring respond, both behaviorally and physiologically, to a challenge later in life. The objectives of this study were to first, determine if elevated maternal glucocorticoid concentrations during late gestation affect the behavioral and physiological response of the female offspring to a challenge during early adolescence, and secondly, determine if giving ketamine (an anxiolytic drug) effects these behavioral and physiological responses. During late gestation (d 76 until 115) sows were either repeatedly injected with ACTH (n = 7) or control handled (n = 7). Three female offspring from each sow were used in the study. A back test was performed on all experimental pigs during the first week of life. Pigs were tested in a novel arena (n = 21/treatment) and social confrontation test (n = 10/treatment) at 25 and 28 wk of age respectively, to assess anxiety-like behaviors. Two h prior to testing in the novel arena and social confrontation tests, pigs were given either ketamine (KET) or saline (SAL). The same pigs were then re-tested 7 d later and given the alternative drug treatment. Hypothalamic-pituitary adrenal function in response to an ACTH challenge and a social confrontation test was assessed. ACTH sows tended to have fewer (P = 0.057) stillborn pigs than controls (0.4 and 0.0 ± 0.14 pigs, respectively). In response to the novel arena test, ACTH pigs tended (P = 0.056) to cross fewer squares than controls (77.2 ± 6.71 and 93.5 ± 93.5 squares, respectively), and pigs given ketamine spent less (P < 0.05) time performing escape behaviors compared to pigs given saline (log-transformed, 0.0 and 0.3 ± 0.11, respectively). In a social confrontation test, ACTH pigs spent more (P < 0.05) time performing mounting behaviors than control pigs (log-transformed, 1.3 and 0.5 ± 0.41, respectively). Furthermore, ACTH pigs given ketamine spent more (P < 0.05) time nudging their pen-mate than ACTH pigs given saline (log-transformed, 3.9 ± 0.29 and 2.9 ± 0.27, respectively). Plasma cortisol concentrations in response to the social confrontation test were lower (P < 0.05) in ACTH pigs given ketamine than ACTH pigs given saline (log-transformed, 1.9 ± 0.37 and 2.7 ± 0.23, respectively). These results suggest that exposure to elevated maternal glucocorticoids and ketamine can affect the behavioral and physiological reactivity of pigs in response to a challenge during early adolescence, and ketamine effects behavioral reactivity of control and prenatally stressed pig's differentially.