TGFβ3, a multifunctional cytokine, was reported as a direct critical driver of tumor growth and metastasis in numerous cancers. Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the molecular mechanisms underlying the tumor-promoting properties of TGFβ3 and CAFs in head and neck cancer (HNC) remain unclear. Here, we show that CAFs isolated from HNC produce significant amounts of TGFβ3 and IL-6. CAFs enhances the growth and metastasis of HNC cells through the secretion of TGFβ3that induces the expression of periostin (POSTN) in HNC cells. Our results indicated that POSTN was significantly up-regulated in HNCs, especially in the tissues with lymph node metastasis. Moreover, POSTN was highly enriched in the stroma of cancer tissues and produced mainly by CAFs. More importantly, we have pinpointed TGF-β3 as the major upstream molecular that triggers the induction of POSTN in CAFs. As such, during the interaction between fibroblasts and cancer cells, the increased stromal POSTN induced by TGF-β3 directly accelerated the growth, migration and invasion of cancer cells. Hence, our study has provided a novel modulative role for POSTN on HNC progression and further reveals POSTN as an effective biomarker to predict metastasis as well as a potential cancer therapeutic target. This work was supported by the National Program on Key Research Project of China (2016YFC0902700) and the National Natural Science Foundation of China (81472572 and 91229103).