Bile acids are known to initiate intricate signaling events in a variety of tissues, primarily in the liver and gastrointestinal tract. Of the known bile acids, only the dihydroxy species, deoxycholic acid and chenodeoxycholic acid (CDCA), and their conjugates, activate processes that stimulate epithelial Cl^- secretion. We have previously published that CDCA acts in a rapid manner to stimulate colonic ion secretion via protein kinase A (PKA)-mediated activation of the dominant Cl^- channel, the cystic fibrosis transmembrane conductance regulator (CFTR) (AJP 305:C447-56, 2013); however, PKA signaling did not account for the entire CDCA response. Here we show that in human colonic T84 cells, CDCA's induction of CFTR activity, measured as changes in short-circuit current (I_sc), is dependent on epidermal growth factor receptor (EGFR) activation, and does not involve the bile acid receptors TGR5 or FXR. CDCA activation of Cl^- secretion does not require Src, mitogen activated protein kinases, or phosphoinositide-3 kinase downstream of EGFR, but does require an increase in cytosolic Ca²⁺. In addition to PKA signaling, we found that the CDCA response requires a novel involvement of the exchange protein directly activated by cAMP (EPAC). EPAC is a known hub for cAMP and Ca²⁺ cross talk. Downstream of EPAC, CDCA activates Rap2, and changes in [Ca²⁺]_i were dependent on both EPAC and EGFR activation. This study establishes the complexity of CDCA signaling in the colonic epithelium, and shows the contribution of EGFR, EPAC and Ca²⁺ in CDCA-induced activation of CFTR-dependent Cl^- secretion.