Histone deacetylase 6 (HDAC6) regulates many physiological processes that are involved in cancer development and progression such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, by deacetylation of multiple substrates and association with interacting proteins. Due to its the ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cells survival. HDAC6 is often overexpressed in tumors, including colorectal cancer (CRC) and is correlated with poor disease prognosis. However, it has been shown in animal models that HDAC6 is not essential for normal mammalian development. Therefore, it represents a good target for the development of novel cancer therapeutics. Selective inhibition of HDAC6 impairs growth and progression of many tumors without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown potential to reduce tumor progression and to enhance the therapeutic effect of other drugs. As HDAC6 is involved in regulation of immune responses, HDAC6 inhibitors have shown potential to improve antitumor immunity by increasing immunogenicity of tumor cells, augmenting immune cell activity and alleviating immunosuppression in tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect and to overcome resistance to immunotherapy.