The cellular response to hypoxia is driven by hypoxia-inducible factors (HIFs), which regulate genes involved in glycolysis, angiogenesis, and cell proliferation, as well as inflammation and tumor progression. HIF activation is well-characterized and is primarily regulated by oxygen-dependent prolyl hydroxylation and subsequent degradation. SET1B, a histone H3 lysine 4 (H3K4) methyltransferase, has recently emerged as a key modulator of HIF target gene transcription, but evidence suggests that it plays a broader role in modulating HIF transcriptional activity beyond histone methylation. Here, we revealed that SET1B interacts with RNA polymerase II to coordinate sustained HIF-mediated transcriptional activity through multiple functional domains. In clear cell renal cell carcinoma (ccRCC), SET1B was critical for sustained HIF activity, and SET1B expression correlated with disease progression and metastasis in patient samples. Moreover, SET1B depletion enhanced the efficacy of HIF-2 inhibitors. These findings establish SET1B as a driver of tumor progression and potential therapeutic target in ccRCC.