Rheumatoid arthritis (RA) is a major autoimmune disease characterized by significant joint inflammation and bone destruction. Many first-line RA treatment drugs such as methotrexate (MTX) have limited solubility in major solvents and are difficult to be delivered to RA joints in a sustained manner. Meanwhile, the efficient co-delivery of osteoinductive ions such as magnesium ions (Mg) for RA treatment is also challenging due to the uncontrolled burst release. By capitalizing on the enhanced supramolecular interactions of cyanuric acid (CYA) upon the pH-induced keto-enol tautomerization, a supramolecular hydrogel (Gel-MTX/Mg) with efficient co-delivery of MTX and Mg is proposed. This hydrogel features pH-responsive on-demand release of MTX and Mg in RA joints triggered by the pathological pH-induced keto-enol tautomerization of CYA. The release of MTX and Mg from the Gel-MTX/Mg hydrogel induces anti-inflammatory M2 macrophage polarization, inhibits osteoclast differentiation, and enhances osteoblastic differentiation. Furthermore, RNA-seq results reveal that the Gel-MTX/Mg hydrogel promotes the enrichment of signaling pathways related to anti-inflammatory and bone-remodeling activities. One-time intra-articular administration of the Gel-MTX/Mg hydrogel significantly suppresses inflammation symptoms and protects bone and cartilage in a rat model. This supramolecular hydrogel that is capable of simultaneously delivering both therapeutic drugs and ions in response to pathological conditions has promising potential for the treatment of RA and other inflammatory and bone-degenerative diseases.