There is evidence that hypoglycemic stress can interact with other stressors, and that ketamine can mitigate the impact of these stressors on behavior and physiology. The current study in male Sprague-Dawley rats investigated whether pre-treatment with 0, 10, or 20 mg/kg ketamine could modulate the interaction between hypoglycemia induced by 0 or 300 mg/kg 2-deoxy-D-glucose (2-DG) and the psychophysical stress of forced swimming (FSS; 6 sessions, 10 min/session) on serum concentrations of corticosterone (CORT) and the pro-inflammatory cytokine, tumor necrosis factor (TNF)-α. It was found that 2-DG enhanced the CORT response to an initial session of FSS, and this effect dissipated after multiple sessions. More importantly, animals displayed significantly higher levels of CORT and lower levels of TNF-α in response to a drug-free test swim conducted 1 week after exposure to the combined stressors, and these responses were not observed in rats that were pre-treated with ketamine. Overall, these findings indicate that ketamine has the potential to reduce the negative impact of interacting stressors on the biological reactivity of the hypothalamic-pituitary-adrenal axis and the immune system.