Background: Human papillomavirus (HPV)–mediated oropharyngeal squamous cell carcinoma (OPSCC) is driven in part by aberrant activation of the BRD4–MYC transcriptional axis, contributing to tumour progression and treatment resistance. While direct MYC targeting remains challenging, BRD4 inhibition represents a viable indirect strategy. AZD5153, a potent bivalent BRD4 inhibitor, has demonstrated clinical safety but has not been evaluated in HPV‑mediated OPSCC. Hypothesis: We hypothesised that BRD4–MYC axis inhibition with AZD5153 would suppress HPV oncogene expression and promote ferroptosis mediated cisplatin sensitisation in HPV positive OPSCC. Methodology: HPV positive OPSCC models were studied using 2D and 3D in vitro systems and cellular xenografts. Integrated transcriptomic and proteomic analyses identified AZD5153 regulated pathways, while Reactive oxygen species (ROS), ferroptosis markers, and cisplatin sensitivity were assessed using biochemical assays and rescue experiments in vitro and in vivo. Results: AZD5153 selectively inhibited HPV‑positive OPSCC growth across all models. Integrated multi‑omics analyses identified a distinct 18‑gene HPV regulatory signature that was significantly downregulated following BRD4 inhibition (p < 0.0001). Proteomic profiling revealed significant upregulation of p62 (SQSTM1) and additional ROS‑regulatory proteins, accompanied by lipid peroxidation, GPX4 downregulation, and intracellular iron accumulation (p < 0.0001). These effects were reversed by N‑acetylcysteine and ferrostatin‑1, confirming ROS‑dependent ferroptotic cell death. AZD5153‑induced ferroptosis significantly sensitized HPV‑positive OPSCC cells to cisplatin, with combination therapy demonstrating synergistic cytotoxicity and overcoming cisplatin resistance in vitro and in vivo (p < 0.0001). Conclusion: BRD4 inhibition with AZD5153 suppresses HPV oncogene expression and primes HPV-mediated OPSCC for ferroptosis-driven chemosensitisation, establishing a strong preclinical rationale for clinical evaluation.