Exercise is recognized to increase the expression of neurotrophic genes in the hippocampus and prevent cognitive impairment. Histone deacetylase (HDAC) inhibitor acetylate histones and enhance gene transcription in epigenetic regulation. HDAC inhibitors are expected to be an efficacious pharmacological treatment for cognitive function. This study aimed to examine the effect of HDAC inhibitors and exercise on epigenetic markers and neurotrophic gene expression in the hippocampus to find a more enriched brain conditioning for cognitive function based on the synergic effects of pharmacological treatment and behavioral therapy. Thirteen-week-old male mice were divided into four groups. Intraperitoneal administration of an HDAC inhibitor (1.2 g/kg sodium butyrate, NaB) and treadmill exercise (approximately 10 m/min for 60 min) were performed 5 days a week for 4 weeks. NaB administration increased the expression of an immediate-early gene, a neurotrophin, and a neurotrophin receptor in the hippocampus. These results indicate that HDAC inhibition could present an enriched platform for neuronal plasticity in the hippocampus and cognitive function. The novel object recognition test showed that NaB administration increased the score. Notably, the step-through passive avoidance test showed improved learning and memory in the presence of exercise and exercise, indicating that the mice acquired fear memory, specifically in the presence of NaB administration plus exercise. This study found that repetitive administration of HDAC inhibitors improved cognitive function and HDAC inhibitor administration plus exercise has a synergic effect on learning and memory, accompanying the enhancement of crucial gene transcriptions for neuronal plasticity in the hippocampus.