Intestinal goblet cells secrete mucus layers protecting the intestinal epithelia against injuries. It is challenging to study the interaction of goblet cells, mucus layers, and gut microbiota because of difficulty in producing goblet cells and mucus models. We generate intestinal goblet cells from human epidermal stem cells with two small molecular inhibitors Repsox and CHIR99021 in the presence of basic fibroblast growth factor and bone morphogenetic protein 4 at high efficiency (~95%) of conversion for a short time (6 to 8 days). Induced goblet cells are functional to secrete mucus, deliver fluorescent antigen, and form mucus layers modeling the mucus-microbe interaction in vitro. Transplantation of induced goblet cells and oral administration of chemical induction media promote the repair of the intestinal epithelia in a colitis mouse model. Thus, induced goblet cells can be used for investigating mucus-microbe interaction, and chemical cocktails may act as drugs for repairing the intestinal epithelia.