Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), an anion channel providing a major pathway for Cl^- and HCO₃^- efflux across the apical membrane of epithelium. In intestine, CF manifests as obstructive syndromes, dysbiosis, inflammation and an increased risk for gastrointestinal cancer. Cftr knockout (Cftr KO) mice recapitulate CF intestinal disease including intestinal hyperproliferation. Previous studies using Cftr KO intestinal organoids (enteroids) indicated that the crypt epithelium maintains an alkaline intracellular pH (pH_i). We hypothesized that Cftr has a cell-autonomous role in down-regulating pH_i that is incompletely compensated by acid-base regulation in its absence. Here, BCECF microfluorimetry of enteroids showed that Cftr KO crypt epithelium sustains an alkaline pH_i and resistance to cell acidification relative to wild-type (WT). Quantitative real-time PCR revealed that Cftr KO enteroids exhibit down-regulated transcription of base (HCO₃^-)-loading proteins and up-regulation of the basolateral membrane HCO₃^--unloader anion exchanger 2 (Ae2). Although Cftr KO crypt epithelium had increased Ae2 expression and Ae2-mediated Cl^-/HCO₃^- exchange with maximized gradients, it also had increased intracellular Cl^- concentration ([Cl^-]_i) relative to WT. Pharmacological reduction of [Cl^-]_i in Cftr KO crypt epithelium normalized pH_i which was largely Ae2 dependent. We conclude that Cftr KO crypt epithelium maintains an alkaline pH_i as a consequence of losing both Cl^- and HCO^3- efflux which impairs pH_i regulation by Ae2. Retention of Cl^- and an alkaline pH_i in crypt epithelium may alter several cellular processes in the proliferative compartment of the Cftr KO intestine.