Osteoarthritis (OA) is a heterogeneous disease that is consistently difficult to treat due to the complexity of the regulatory network involved in OA pathogenesis, especially in terms of cartilage degeneration. As a C-2 epimer of glucose, d -mannose can alleviate bone loss and repress immunopathology by upregulating regulatory T cells; however, the role of d -mannose in OA-related cartilage degeneration remains unknown. In this study, we investigated the chondroprotective effect of d -mannose in vitro and in vivo on OA. We found that incubating interleukin (IL)-1β-treated rat chondrocytes with d -mannose restrained OA degeneration by elevating cell proliferation, strongly activating autophagy, reducing apoptosis, and downregulating catabolism. Additionally, oral gavage administration of d -mannose to monosodium iodoacetate (MIA)-treated rats revealed that a median (1.25 g/kg/day) rather than high or low dose of d -mannose suppressed OA progression and attenuated OA development based on lower macroscopic scores for cartilage, decreased histological scores for cartilage and synovium, strongly activated autophagy, and downregulated catabolism. In terms of a downstream mechanism, we showed that d -mannose might attenuate OA degeneration by activating autophagy in IL-1β-treated rat chondrocytes by promoting the phosphorylation of 5′ AMP-activated protein kinase (AMPK). Our in vitro findings revealed that d -mannose delayed IL-1β-induced OA degeneration in rat chondrocytes by enhancing autophagy activation through the AMPK pathway. Furthermore, the in vivo results indicated that a median dose of d -mannose suppressed MIA-induced OA development. These results suggested that d -mannose exhibits chondroprotective effects and represents a potential disease-modifying drug and novel therapeutic agent for OA.