Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we provide mechanistic basis of changes in β-catenin/APC/CKIɛ leading to progression and/or regression of hyperplasia in vivo. In response to CR-induced TMCH, crypt lengths increased significantly between days 6–27 post-infection, followed by a steep decline by day 34. β-Cat⁴⁵/total β-catenin were elevated on day 1 post-infection, preceding changes in crypt length, and persisted for 27 days before declining by day 34. Importantly, cellular CKIɛ and β-catenin co-immunoprecipitated and exhibited remarkable parallel changes in kinetics during hyperplasia/regression phases. β-catenin, phosphorylated at Ser33,37 and Thr41 (β-cat^33,37/41), was low till day 12, followed by gradual increase until day 27 before declining by day 34. GSK-3β exhibited significant Ser⁹-phosphorylation/inactivation at days 6–12 with partial recovery at days 27–34. Wild type (wt) APC (p312) levels increased at day 6 with transient proteolysis/truncation to p130 form between days 12 and 15; p312 reappeared by day 19 and returned to baseline by day 34. The kinetics of β-Cat⁴⁵/β-catenin nuclear accumulation and acetylation (Ac-β-Cat^Lys49) from days 6 to 27, followed by loss of phosphorylation/acetylation by day 34 was almost identical; Tcf-4 co-immunoprecipitated with β-Cat⁴⁵/β-catenin and localized immunohistochemically to β-Cat^41/45-positive regions leading to elevated cyclin D1 expression, during the hyperproliferative, but not regression phases of TMCH. CKIɛ mediated phosphorylation of β-Cat⁴⁵, resulting in stabilization/nuclear translocation of β-Cat⁴⁵ may be critical for maintaining proliferation at days 6–27. Reversal of GSK-3β phosphorylation and APC changes may be equally critical during the regression phase from days 27 to 34.