Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with approximately 890,000 new cases diagnosed annually. Standard-of-care management involves surgery followed by radiotherapy and/or chemotherapy. While tumour fibrosis can limit therapeutic response, treatment-induced fibrosis is also a common complication following surgery and radiotherapy in HNSCC. Fibrosis is largely driven by dysregulation of the Rho-ROCK signalling pathway. This study explored the benefit of combining an anti-fibrotic small molecule ROCK2 inhibitor, RX10616, with radiotherapy in patient-derived models of HNSCC. Analysis of patient tissue samples found that 35% (39/110) of HNSCC patients had highly fibrotic tumours (>10% medium staining; picrosirius red staining) and correlated to poorer recurrence-free survival. ROCK1/2 staining was associated with highly fibrotic tumours demonstrating the role of Rho-ROCK signalling in HNSCC fibrosis. In vitro, RX10616 decreased patient-derived cancer-associated fibroblast-mediated collagen contraction (collagen contraction assay) and decreased cancer cell invasion (organotypic invasion assay) which was further decreased when combined with radiotherapy. In patient-derived xenograft mouse models, RX10616 (50mg/kg 5days on/2days off orally) combined with radiotherapy (2Gy) significantly increased mouse survival compared to radiotherapy alone. Notably, in two of the three models, 40% (2/5) mice achieved complete tumour regression. Tumours treated with combination therapy had reduced collagen deposition (picrosirius red staining) and decreased hypoxia (reduced HIF1 expression) compared to radiotherapy alone. This study demonstrates that RX10616, a ROCK2 inhibitor, effectively reduces tumour fibrosis and enhances radiotherapy efficacy in HNSCC. These findings support clinical translation of ROCK2 inhibition as a radio-sensitizing strategy for fibrotic HNSCC tumours.