Herbs are an increasingly popular treatment option for horses with cartilage inflammation, despite a relative paucity of research demonstrating efficacy. The research objective was to evaluate the differential anti-inflammatory and chondroprotective efficacy of a simulated digest of indomethacin and a commercially available herbal product in a cartilage model of osteoarthritis. Cartilage explant was integrated with simulated digestion of indomethacin and the herbal product in order to account, at least in part, for the actions of major digestive enzymes and pH. The resulting digests were ultrafiltrated (50 kDa), to account for absorption from the GI tract and movement into the cartilage matrix. We hypothesized that (i) a simulated digest of indomethacin would block interleukin 1 beta-(IL-1) dependent formation of prostaglandin E2 (PGE2) and nitric oxide (NO) without protecting cartilage against IL-1-induced glycosaminoglycan (GAG) release, and (ii) the herbal product would reduce PGE2 and NO in IL-1-stimulated explants, and inhibit release of GAG, in IL-1-stimulated explants. Results showed that indomethacin is an effective anti-inflammatory, evidenced by strong inhibition of IL-1-induced PGE2 and NO from cartilage explants. However, indomethacin provided no protection against IL-1-induced GAG release. Simulated digest of the herbal extract significantly inhibited IL-1-induced NO production and GAG release, while having a slight increase in PGE2. These data provide evidence for the anti-inflammatory effect of indomethacin on IL-1-stimulated cartilage explants, and the herbal product Mobility may be a useful adjunct in arthritis because of its chondroprotective properties in IL-1-stimulated cartilage.