Type 2 diabetes (T2D) is epidemiologically associated with colorectal cancer (CRC) and both T2D and CRC are linked with Vitamin D (VD) deficiency. How VD may affect the molecular mechanisms linking T2D and CRC is a key issue. The most prominent feature of CRCs is abnormal Wnt/β-catenin signaling, which remarkably is facilitated by hyperglycemia in T2D. Thus, high glucose increases the levels and activity of the acetyl-transferase EP300 that, in turn, promotes β-catenin acetylation. Of note, together with Wnt signaling, β-catenin acetylation promotes its nuclear accumulation and activity. Previously, Calcitriol (1,25(OH)2D3), the most active form of VD, was found to engage its high affinity receptor (VDR) to outcompete β-catenin leading to decreased expression of Wnt targets such as E-cadherin or DKK1. However, how VD/Calcitriol impacts β-catenin signaling in CRC remained poorly understood. Here we reveal that calcitriol-bound VDR reverses the effects of hyperglycemia to exclude β-catenin from the nuclei of CRC cells through induction of the deacetylase Silent Information Regulator of Transcription, sirtuin 1 (SIRT1). SIRT1 is an NAD+-dependent epigenetic modifier whose activity is associated with healthy aging and longevity. Mechanistically, calcitriol-bound VDR increased the expression of- and interacted with- SIRT1 to cause its auto-deacetylation on Lys610 and activation, highlighting Lys610 as an essential driver of SIRT1 catalytic activity. Moreover, calcitriol facilitated the interaction of SIRT1 with- and deacetylation of- β-catenin to drive its nuclear exclusion and the subsequent downregulation of pro-tumourigenic target genes. Depletion or inhibition of SIRT1 abolished calcitriol-induced interference of Wnt/β-catenin signaling, whereas orthogonal activation of SIRT1 mimicked calcitriol effects and restored the antitumoral response in VD-resistant cells. SIRT1 appears as a crucial mediator in the protective action of VD against CRC and suggest a therapeutic potential for SIRT1 activators (downstream of VDR) in patients with advanced CRCs that tend to lose VDR expression. The results highlight post-translational modifications of epigenetic modifiers as flexible and timely mechanisms for rapid adaptations to the dynamic environment of cancer cells. Moreover, since nuclear localization of β-catenin is a critical driver of CRC that requires its acetylation, we provide a mechanistic foundation for the epidemiological evidence linking vitamin D deficiency with increased T2D and CRC risk and mortality. The molecular mechanism uncovered may explain the association between T2D and CRC, and potentially other cancers (eg melanoma) with an association between VD deficiency and T2D.