Osteoarthritis (OA) is a debilitating multifactorial joint disease lacking effective disease-modifying OA drugs (DMOADs). High failure rates for clinical trials in OA could be due to inadequate screening approaches that rely on single target strategies and late-stage disease models, completely bypassing the critical therapeutic window of early OA. To overcome these translational bottlenecks, we developed a robust interleukin 1β (IL1β)-induced ex vivo early OA screening platform and targeted hypoxia inducible factor 2α (HIF-2α), an upstream regulator of early catabolic OA hallmarks. Using caprine cartilage explants, an early OA-like phenotype was established by optimizing IL1β exposure (1 ng/mL for 48 h). The model’s translational relevance was validated against human OA samples by assessing sulphated glycosaminoglycans (sGAG) depletion, and expression profiles of inflammatory, hypertrophic, senescent and matrix degrading markers. The developed model demonstrated phenotypic and molecular signatures closely recapitulating human early OA pathology. Further, treatment with known pharmacological agents (Celecoxib and Rapamycin) successfully rescued the OA phenotype, confirming the model’s predictive validity. Utilizing this model, we evaluated TC-S 7009 (TCS), a specific HIF-2α inhibitor, as a potential DMOAD. TCS treatment effectively rescued sGAG loss, restored the expression of matrix markers and significantly reduced matrix degrading enzymes. This study establishes an IL1β-induced ex vivo platform for early OA drug screening and identifies TCS as a promising, stage-specific DMOAD candidate. Importantly, it demonstrates that aligning therapeutic targets (HIF-2α) with appropriate pathological stage (early OA) is a useful strategy for successful pharmacotherapy identification in OA.