Glucagon-like peptide 2 (GLP-2) stimulates intestinal growth, repairs mucosa, and enhances epithelial integrity but has a short half-life (7 min). Glepaglutide (GL), a GLP-2 analog with an extended half-life (50 h), is currently undergoing clinical trials for patients with short bowel syndrome. GL requires subcutaneous injection, which poses challenges for potential patient compliance. To address this challenge, GL was loaded into a rectal foam formulation using CO as a permeation enhancer to combine both the local and systemic effects of the GLP-2 analog. In a dextran sodium sulfate (DSS)-induced colitis model, the GL-loaded foam (GLF) significantly mitigated the severity of colitis. GLF facilitated mucosal healing, as evidenced by colonoscopy images, increased plasma markers of mucosal healing, and increased crypt depth. To evaluate GL absorption in the colon, fluorescein dextran 4K (FD 4K) was employed. The foam formulation improved macromolecule absorption in the colon, with fast recovery of enhanced permeation that dissipated after 4 h. This study highlights GLF as a promising formulation for GL administration, balancing systemic and local anti-inflammatory effects.