PURPOSE: To investigate the role of neuregulin (NRG) signaling in promoting head and neck squamous cell carcinoma (HNSCC) migration through HER3-dependent pathways and to assess the therapeutic potential of targeting the NRG/HER3 axis in mitigating perineural invasion. METHODS: NRG-driven migration was studied using DRG co-culture, wound healing assays, and HER3 inhibition (shRNA, AV-203). The biological function and biochemical effects of the HER3/HER2/FAK axis in response to NRG were analyzed via phosphorylation assays, knockdown, western blotting, and cell staining for protein expression. RESULTS: NRG promoted directional migration of FaDu and TU138 HNSCC cells through HER3/HER2 and HER3/PI3K interactions. HER3 inhibition (shRNA or AV-203) abolished HER3 phosphorylation, disrupted HER3-HER2 interactions, and suppressed AKT and ERK signaling. Wound healing assays confirmed that NRG enhances migration via HER3 activation. NRG also induced HER3-dependent FAK phosphorylation, and FAK knockdown or inhibition with PF228 significantly reduced NRG-driven migration, highlighting the critical role of HER3-FAK signaling. CONCLUSION: NRG promotes HNSCC cell migration by activating HER3, forming HER3-HER2 and HER3-FAK complexes, and driving downstream AKT, ERK, and FAK signaling. Targeting the NRG/HER3 axis holds potential as a therapeutic strategy to address perineural invasion and associated clinical challenges in HNC.