The treatment of prolonged inflammation and cartilage damage due to osteoarthritis (OA) is a major clinical challenge. We developed a comprehensive cartilage repair therapy using a dual drug-loaded nanocomposite hydrogel that leveraged the spatiotemporal immunomodulatory effects of a naturally degradable protein-based nanocomposite hydrogel. The hydrogel acted as a scaffold that created a favorable microenvironment for cartilage regeneration. The hydrogel recruited macrophages and human mesenchymal stem cells (hMSCs), which supported the growth and adhesion of osteoblasts, and degraded to provide nutrition. Silk protein nanoparticles were chemically cross-linked with kartogenin, and human-like collagen was physically cross-linked with dexamethasone through hydrogen bonding. In the early stages of cartilage repair, a large quantity of dexamethasone was released. The dexamethasone acted as an anti-inflammatory agent and a spatiotemporal modulator of the polarization of M1 macrophages into M2 macrophages. In the middle and late stages of cartilage repair, kartogenin underwent sustained release from the hydrogel, inducing the differentiation of hMSCs into chondrocytes and maintaining chondrocyte stability. Therefore, kartogenin and dexamethasone acted synergistically to induce cartilage repair. In conclusion, we developed an integrated therapeutic system by constructing a cartilage regeneration microenvironment and inducing synergistic drug-based cartilage regeneration. The therapeutic system demonstrated satisfactory efficacy for repairing cartilage damage in rabbits.