As an intracellular pattern recognition receptor (PPR), the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) triggers a cascade of immune responses. Previous studies of NOD2 regarding inflammatory bowel disease (IBD) mainly focused on the relevance of NOD2 mutations and loss within the disease onset and progression. With increasing research, more studies are exploring other functional roles and clinical applications of NOD2. In this review, we discuss the role of NOD2 in intestinal immune response and microbiota modulation in IBD and explore its clinical potential as a therapeutic target for IBD.