Chronic inflammatory diseases, such as endometriosis (EMS) and rheumatoid arthritis (RA), share a common pathogenic hallmark driven by a hyperinflammatory microenvironment. Nonetheless, long-acting therapeutic platforms capable of concurrently addressing these disparate disorders remain rarely explored. Herein, we developed a leonurine microcrystal-encapsulated microcomposite depot (Leo-micro@MD) capable of effectively mitigating inflammation, thereby reversing the progression of both EMS and RA. Systemic formulation optimization yielded an optimized Leo-micro@MD formulation with high drug loading and a sustained, burst-free release profile extending over 18 days, markedly reducing administration frequency. Mechanistically, Leo-micro@MD suppresses key upstream inflammatory cytokines, thereby branching into distinct downstream therapeutic pathways tailored to each disorder. In EMS, this reduction attenuated estrogen-ERα signaling and restored progesterone receptor B (PRB) expression, subsequently reactivating LC3B-mediated autophagy and Bax/Bcl-2-dependent apoptosis to eradicate ectopic lesions. Concurrently, in an adjuvant-induced arthritis rat model, this anti-inflammatory cascade attenuates synovial hyperplasia, rescues bone mineral density and trabecular architecture, and re-establishes articular matrix homeostasis, as confirmed by micro-CT and comprehensive histopathology. Importantly, these disease-modifying effects are achieved with an excellent systemic safety profile, with no detectable hepatotoxicity, nephrotoxicity, or immune organ damage. Collectively, this study provides a robust and translatable controlled-release strategy for the comprehensive management of chronic inflammatory diseases.