It has been suggested that Alzheimer's disease (AD), a progressive neurological condition, can potentially be treated through epigenetic means by targeting histone deacetylases (HDACs), enzymes that regulate gene expression. In this study, we investigated the molecular mechanisms of Bufexamac, in an animal model of AD. Bufexamac specifically targets Class IIb HDACs, which are particularly relevant in the context of neuroinflammation and neurodegeneration. This selectivity may reduce off-target effects commonly associated with broader-spectrum HDAC inhibitors, such as pan-HDAC inhibitors, which can affect multiple HDAC classes and potentially lead to undesirable side effects. Male rats injected with Aβ25–35 for AD-like symptoms were treated with 20 μg/rat Bufexamac for 8 days. Cognitive function, depression, and anxiety were assessed through behavioral tests, while Western blotting, H&E staining, and ELISA were used to detect protein expression, morphological changes, and enzyme activity. Bufexamac treatment markedly improved cognitive and behavioral impairments in Aβ-injected rats and regulated the key proteins related to neuroinflammation (GFAP, Iba1), histone, and α-tubulin acetylation. Simultaneously, it decreased the expression of proteins in the stromal interaction molecule (STIM) pathway. Furthermore, Bufexamac lowered the activity of monoamine oxidase enzymes, elevated the count of healthy neurons, and ameliorated neuronal structure in the hippocampus. Overall, these findings suggest that Bufexamac could be a more targeted therapy for AD than other non-selective HDAC inhibitors, which often have diverse functions and potential side effects. Bufexamac enhances cognitive function and alleviates depression and anxiety by regulating proteins related to neuroinflammation, histone, and α-tubulin acetylation, as well as modulating STIM levels and MAO activity.