Solid tumors contain extensive hypoxic areas and it is of considerable importance to decipher the potential role of hypoxia in signaling pathway regulation. In the present study, we examined the impact of hypoxia on β‐catenin status and the mechanisms involved. Hypoxia significantly decreased β‐catenin protein, but had no effect on glycogen synthase kinase (GSK)‐3β or adenomatous polyposis coli (APC) levels. However, hypoxia‐induced β‐catenin downregulation seemed to require APC but not GSK‐3β. Further investigation revealed that hypoxia significantly upregulated Siah‐1, the human homolog of Drosophila seven in absentia. In addition, hypoxia augmented the interaction between β‐catenin and SIP and Skp1. Silencing of Siah‐1, as well as the use of a dominant negative Siah‐1 mutant, attenuated these responses to hypoxia and rescued β‐catenin transactivation. The Siah‐1‐mediated degradation of β‐catenin during hypoxia may involve p53, but not hypoxia‐inducible factor‐1, activation. Together, the results suggest that hypoxia downregulates β‐catenin by increasing Siah‐1 expression in a p53‐dependent manner. (Cancer Sci 2011; 102: 1322–1328)