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Osteoarthritis (OA) is a progressive disease that causes pain, stiffness, and inflammation in the affected joints. Currently, there are no effective treatments for preventing the worst outcomes, such as synovitis or cartilage degradation. <i>Sarcodia montagneana</i> and <i>Corbicula fluminea</i> are common species found in the ocean or in freshwater areas. Their extracts are demonstrated to possess both antioxidative and anti-inflammatory functions. This study aimed to investigate the synergistic effects of the extracts of <i>Sarcodia montagneana</i> (SME) and <i>Corbicula fluminea</i> (FCE) on reducing local and systemic inflammation, as well as their efficacy in OA symptom relief. An in vitro monocytic LPS-treated THP-1 cell model and in vivo MIA-induced mouse OA model were applied, and the results showed that the combinatory usage of SME and FCE effectively suppressed IFN-<i>γ</i> and TNF-α production when THP-1 cells were treated with LPS. SME and FCE also significantly decreased the systemic TNF-α level and joint swelling and prevented the loss of proteoglycan in the cartilage within the joints of OA mice. The data shown here provide a potential solution for the treatment of osteoarthritis.