It has been hypothesized that apically expressed L-type Ca²⁺ channel Ca_v1.3 (encoded by CACNA1D gene) contributes towards an alternative TRPV6-independent route of intestinal epithelial Ca²⁺ absorption, especially during digestion when high luminal concentration of Ca²⁺ and other nutrients limit TRPV6 contribution. We and others have implicated altered expression and activity of key mediators of intestinal and renal Ca²⁺ (re)absorption as contributors to negative systemic Ca2+ balance and bone loss in intestinal inflammation. Here, we investigated the effects of experimental colitis and related inflammatory mediators on colonic Ca_v1.3 expression. We confirmed Ca_v1.3 expression within the segments of the mouse and human gastrointestinal tract. Consistent with available microarray data (GEO database) from IBD patients, mouse colonic expression of Ca_v1.3 was significantly reduced in TNBS colitis. In vitro, IFN most potently reduced Ca_v1.3 expression. We reproduced these findings in vivo with wild-type and Stat1^-/- mice injected with IFN. The observed effect in Stat1^-/- suggested a non-canonical transcriptional repression or a post-transcriptional mechanism. In support of the latter, we observed no effect on the cloned Ca_v1.3 gene promoter activity, and accelerated Ca_v1.3 mRNA decay rate in IFN-treated HCT116 cells. While the relative contribution of Ca_v1.3 to intestinal Ca²⁺ absorption and its value as a therapeutic target remain to be established, we postulate that Ca_v1.3 downregulation in IBD may contribute to the negative systemic Ca²⁺ balance, increased bone resorption, and to reduced bone mineral density in IBD patients.