Osteoarthritis (OA) a disease associated with joints and become severe with age, due to softening, inflammation and degradation of cartilage in joints. The agents that can target OA is needed, specifically without any side effects. Garcinia mangostana L. (Mangosteen) a tropical fruit used to treat many skin and stomach associated ailments. γ- Mangostin (γ-MS) a key bioactive substance present in mangosteen. Here, we aimed to explore γ-MS potential in targeting the pro-inflammatory cytokine, factors and miRs in OA progression. Significantly, γ-MS suppresses the inflammatory cytokines (IL-6, TNF-α, and INF- γ) and factors (NF-κB, STAT3, and COX-2) which regulates/participate in the catabolic process of cartilage destruction. Result of Hematoxylin-eosin (H&E) staining of tissue sections of OA joints of γ-MS treated and non-treated mice confirm γ-MS improves the signs of injuries, and maintains the structural integrity of the articular cartilage (epiphyseal disk joints and bone marrow) and reduces inflammation. Mechanistically, γ-MS targets miR-98-5p and miR-124-3p which are found to suppress the expression IL-6 and NF-κB, respectively. But in OA these miRs are inhibited, especially miR-124-3p which regulates not only NF-κB but also TNF-α, IL-6 and MMP7. With a further investigation underway, γ-MS represents an important source for treating and managing OA.