Wnt signaling is critical to maintaining cellular homeostasis via regulation of cell division, mitigation of cell stress, and degradation. Aberrations in Wnt signaling contribute to carcinogenesis and metastasis, while sirtuins have purported roles in carcinogenesis, aging, and neurodegeneration. Therefore, the hypothesis that sirtuin 2 (SIRT2) directly interacts with β-catenin was tested and whether this interaction alters the expression of Wnt target genes to produce an altered cellular phenotype. Co-immunoprecipitation studies, using mouse embryonic fibroblasts (MEFs) from Sirt2 wild-type and genomic knockout mice, demonstrate that β-catenin directly binds SIRT2. Moreover, this interaction increases in response to oxidative stress induced by ionizing radiation (IR). Additionally, this association inhibits the expression of important Wnt target genes like survivin (BIRC5), cyclin D1 (CCND1), and c-myc (MYC). In Sirt2 null MEFs, an up-regulation of matrix metalloproteinase 9 (MMP9) and decreased E-cadherin (CDH1) expression is observed that produces increased cellular migration and invasion. Together, these data demonstrate that SIRT2, a tumor suppressor lost in multiple cancers, inhibits the Wnt signaling pathway in non-malignant cells by binding to β-catenin and that SIRT2 plays a critical role in the response to oxidative stress from radiation.