Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is an anthraquinone compound mainly isolated from the herbal medicine rhubarb. It possesses a wide spectrum of pharmacological effects. However, the lack of sustained release properties and the poor bioavailability hinder clinical transformation. Hydrogel-based drug delivery system provides an ideal carrier to improve the release control and the therapeutic efficacy of drugs. Herein, we present a chitosan hydrogel for the delivery of rhein. This rhein-chitosan hydrogel (CS-Rh gel) exhibited superior characteristics including mechanical strength, sustained release, and low toxicity. For medical application, the enzyme-linked immunosorbent assay and Western blot analyses indicated that CS-Rh gel significantly suppressed the production of proinflammatory cytokines including TNF-α and IL-1β in lipopolysaccharide-induced BV2 cells. Additionally, CS-Rh gel blocked the neuroinflammation-related mitogen-activated protein kinase (JNK, ERK, and p38)-signaling pathways. Interestingly, these inhibitory effects at 48 h outperformed the pharmacologic actions at 24 h, showing that the CS-Rh gel exerted optimal sustained antineuroinflammation. This study highlights a novel chitosan hydrogel containing rhein used as a potential antineuroinflammatory agent.