Head and neck squamous cell carcinoma (HNSCC) is among the most severe and complex malignant diseases with a high level of heterogeneity and, as a result, a wide range of therapeutic responses, regardless of clinical stage. Tumor progression depends on ongoing co-evolution and cross-talk with the tumor microenvironment (TME). In particular, cancer-associated fibroblasts (CAFs), embedded in the extracellular matrix (ECM), induce tumor growth and survival by interacting with tumor cells. Origin of CAFs is quite varied, and the activation patterns of CAFs are also heterogeneous. Crucially, the heterogeneity of CAFs appears to play a key role in ongoing tumor expansion, including facilitating proliferation, enhancing angiogenesis and invasion, and promoting therapy resistance, through the production of cytokines, chemokines, and other tumor-promotive molecules in the TME. This review describes the various origin and heterogeneous activation mechanisms of CAFs, and biological heterogeneity of CAFs in HNSCC is also included. Moreover, we have highlighted versatility of CAFs heterogeneity in HNSCC progression, and have discussed different tumor-promotive functions of CAFs respectively. In the future, it is a promising strategy for the therapy of HNSCC that specifically targeting tumor-promoting CAF subsets or the tumor-promoting functional targets of CAFs.© 2023. The Author(s).