Histone deacetylase 3 (HDAC3) is a class I HDAC that plays a critical role in chromatin remodeling and gene transcription regulation. It is unique among HDACs due to its ability to shuttle between the nucleus and cytoplasm, allowing it to exert both enzymatic and non-enzymatic functions. HDAC3 primarily functions as a co-repressor, interacting with nuclear receptor co-repressors (NCoR) or silencing mediator of retinoic and thyroid receptors (SMRT) to deacetylate histones and repress gene expression. This activity is crucial for various physiological processes, including embryonic development, circadian rhythms, and metabolism. Additionally, HDAC3 is implicated in several diseases, such as cancer, neurodegeneration, and cardiovascular diseases, making it a target for therapeutic interventions. Its role in inflammation is also significant, as it regulates pro-inflammatory gene expression in macrophages. HDAC3 inhibitors are being explored for their potential in treating these conditions, with specific inhibitors showing promise in reducing side effects compared to general HDAC inhibitors.