G protein-coupled receptors (GPCRs) make up the largest transmembrane receptor superfamily in the human genome and are expressed in nearly all gastrointestinal (GI) cell types. Coupling of GPCRs and their respective ligands activates various phosphotransferase in the cytoplasm, and thus, activation of GPCR signaling in intestine regulates many cellular and physiological processes. Studies in microRNAs (miRNAs) demonstrate that they represent critical epigenetic regulators of different pathophysiologic responses in different organs and cell types in humans and animals. Here, we reviewed recent research on GPCR/miRNA interactions related to GI pathophysiology, such as, Inflammatory Bowel Diseases (IBD), Irritable Bowel Syndrome (IBS) and GI cancers. Given that the presence of different types of cells in the GI tract suggest the importance of cell-cell interactions in maintaining GI homeostasis, we also discuss how GPCR/miRNAs interactions regulate gene expression at the cellular level and subsequently modulate GI pathophysiology through molecular regulatory circuits and cell-cell interactions. These studies helped identified novel molecular pathways, leading to the discovery of potential biomarkers for GI diseases.