Crohn's disease (CD) is a relapsing, systemic inflammatory disease that primarily affects the gastrointestinal tract and is often accompanied by extraintestinal manifestations and associated immune disorders. However, current pharmacological treatments for CD encounter several challenges, such as a lack of precise drug targeting and inadequate retention of drugs in the inflamed colon, along with low bioavailability. Herein, we utilized oleic acid (OA) as a solvent to enhance the bioavailability and solubility of emodin. Simultaneously, we encapsulated OA-emodin (OAE) into hydrogel microspheres (HMs) composed of hyaluronic acid (HA) and calcium alginate (CA) to develop a colon-targeted drug delivery system (HM@OAE) for CD therapy. The pH responsiveness of CA enabled HM@OAE to bypass the stomach and specifically target the colon, where it released OAE following oral administration. In addition, in vitro studies demonstrated that HM@OAE significantly reduced the secretion of proinflammatory cytokines, decreased reactive oxygen species levels, and restrained ferroptosis by upregulating GPX4 and SLC7A11 expression while downregulating ACSL4 expression. Furthermore, to confirm these findings in a live organism, an in vivo study was conducted using a dextran sulfate sodium-induced colitis mouse model. This study validated the therapeutic efficacy of HM@OAE, significantly alleviating colonic inflammation and restoring intestinal epithelial integrity. These results suggest that HM@OAE is a promising clinical candidate for CD treatment.