Osteoarthritis (OA) is the fourth most debilitating multifactorial disease, associated with personal and socioeconomic burdens worldwide. Currently, no safe therapy is available that can effectively prevent the deterioration of cartilage and subchondral bone or reverse existing defects. To address this, we have designed a multitargeted formulation, PL02, consisting of standardized extracts of the Rosa canina L, and Hippophae rhamnoides, along with collagen peptide, to explore the pharmacological efficacy in the Monosodium iodoacetate-induced (MIA) OA model in the rodents. The results show oral administration of PL02 exhibits antioxidant effects via down-regulating NOS, alleviated pain-related behavior, and reduced inflammation via inhibiting IL-1b and dependent TNF-a production, downregulating CGRP1 and COX-II. PL02 exerted anti-catabolic and chondroprotective activity by significantly downregulating MMP13 and upregulating BCL2. PL02 exhibited chondrogenic activity by significantly upregulating SOX-9(master regulator of chondrogenesis), Coll-I, and aggrecan, the major collagen and proteoglycan in the articular cartilage and prevented microarchitectural deterioration of subchondral bone. Thus, orally active PL02, a multi-targeted disease-modifying therapy that has not only alleviated pain and inflammation but also effectively arrested cartilage, and subchondral bone deterioration, constitutes a safe novel candidate for OA treatment and management.