<p>Major Depressive Disorder (MDD) is a multifactorial psychiatric condition. Evidence shows that stress plays a fundamental role in the pathophysiology of MDD. Studies have hypothesized that some changes in histone acetylation patterns and histone deacetylase (HDACs) are closely associated with the development of MDD. Histone acetylation and deacetylation are covalent modifications that influence chromatin structure, serving as key mechanisms for controlling gene expression. The aim of this study was to investigate the involvement of H2AK5ac, H2BK5ac, H3K9ac, and H4K8ac, as well as HDACs, HDAC1-7 in rats subjected to the chronic unpredictable moderate stress (CUMS) model. For this, 29 male Wistar rats were exposed to the CUMS protocol or designated as a control group. After behavioral tests the animals were classified as resilient or susceptible to the depressive-like phenotype. Subsequently, the acetylation patterns of histones and HDACs were evaluated in the hypothalamus, hippocampus, and parietal cortex. Observing sucrose consumption, open field behavior, and object recognition, it is possible to identify characteristic phenotypes of animals that are either susceptible to the depressive-like phenotype or resilient to the CUMS protocol. For the first time, it was demonstrated that the H3K9ac, H4K8ac, HDAC2, HDAC3, HDAC4, and HDAC5 patterns are associated with resilience or susceptibility to the depressive-like phenotype in a brain region-specific manner. Results from this study provide evidence that H3 and H4 acetylation’s and HDACs are connected with the development of the resilient or susceptible depressive-like phenotype, hence contributing to new advances in understanding the pathophysiology of MDD and discovering mechanisms behind resilience.</p>