Chronic stressful occurrences are documented as a vital cause of both depression and anxiety disorders. However, the stress-induced molecular mechanisms underlying the common and distinct pathophysiology of these disorders remains largely unclear. We utilized a chronic mild stress (CMS) rat model to differentiate and subgroup depression-susceptible, anxiety-susceptible, and insusceptible rats. The hippocampus was analyzed for differential proteomes by combining mass spectrometry and the isobaric tags for relative and absolute quantitation (iTRAQ) labeling technique. Out of 2593 quantified proteins, 367 were aberrantly expressed. These hippocampal protein candidates might be associated with susceptibility to stress-induced depression or anxiety and stress resilience. They provide the potential protein systems involved in various metabolic pathways as novel investigative protein targets. Further, independent immunoblot analysis identified changes in Por, Idh2 and Esd; Glo1, G6pdx, Aldh2, and Dld; Dlat, Ogdhl, Anxal, Tpp2, and Sdha that were specifically associated to depression-susceptible, anxiety-susceptible, or insusceptible groups respectively, suggesting that identical CMS differently impacted the mitochondrial and metabolic processes in the hippocampus. Collectively, the observed alterations to protein abundance profiles of the hippocampus provided significant and novel insights into the stress regulation mechanism in a CMS rat model. This might serve as the molecular basis for further studies that would contributed to a better understanding of the similarities and differences in pathophysiologic mechanisms underlying stress-induced depression or anxiety, and stress resiliency.