Hydrogels characterized by a three-dimensional polymer network are promising vehicles for oral colon-targeted drug delivery, yet conventional systems relying on intragastric cross-linking agents face clinical limitations. Here, we present a cross-linker-independent oral in situ hydrogel (CCS/CMC-Na) functionalized with Ti(3)C(2) MXene nanosheets for optimized inflammatory bowel disease (IBD) therapy. The CCS/CMC-Na hydrogel exhibits a liquid-gel state transition in simulated gastric fluids while gradually returning to a liquid state in simulated colonic fluids, enabling precise targeting of inflamed colon tissues and protecting encapsulated drugs from gastric degradation. The integration of Ti(3)C(2) not only enhances mechanical stability but also introduces multifunctional therapeutic capabilities: repairing all levels of intestinal barriers, reducing oxidative stress, inhibiting apoptosis, modulating Regulatory T cells (Treg)/T helper 17 (Th17) cell differentiation and NF-kappaB/IkappaB inflammatory pathway, and remodeling the intestinal microbiota. In murine models of acute and chronic colitis, Ti(3)C(2)@CCS/CMC-Na significantly alleviates disease severity, outperforming clinical first-line drug 5-ASA. Crucially, this system eliminates the need for dual-tube administration, simplifies dosing protocols, and demonstrates excellent biocompatibility over 50 days, addressing key challenges in current IBD therapies. By integrating precise targeting, multimodal therapeutic actions, and scalable fabrication, Ti(3)C(2)@CCS/CMC-Na represents great clinical translational potential, offering a safer and more effective treatment option for IBD.