Macrophage polarization has been known as a critical step in balancing inflammatory responses by creating a balanced plasticity between M1 and M2 macrophages, which act as pro-inflammatory and anti-inflammatory mediators, respectively. Histone deacetylases (HDACs) have been shown to play a vital role in polarization, identifying them as possible contributors and therapeutic targets in metabolic diseases, cancer, inflammatory diseases, and other associated conditions. In this regard, isoform-specific HDAC inhibitors (HDACis) can selectively alter macrophage polarization, thereby overcoming the limitations of pan-HDAC inhibitors and offering therapeutic advantages. Moreover, combining HDAC inhibitors with other therapies has emerged as a promising approach, especially in cancer; however, further studies should determine the specificity of HDAC inhibitors as well as address possible problems in optimizing the bioavailability and reducing off-target effects and cytotoxicity to translate these results into practical therapeutic plans for disorders associated with inflammation.