As a common joint disease, osteoarthritis (OA) is often associated with chronic pain. Synovial inflammation is correlated with OA progression and pain. Synovial inflammation can produce a series of destructive substances, such as inflammatory factors and pain mediators, which aggravate cartilage injury and further accelerate the progression of OA. Although many studies investigated the effects of synovial inflammation on the onset and progression of OA, there are limited reports regarding slowing the progression of OA and relieving pain by modulating synovial inflammation. Therefore, there is an urgent need to search for safe and effective drugs to alleviate synovial inflammation. Dexmedetomidine, a selective α agonist, has been shown to have anti-inflammatory and analgesic effects. However, its role and mechanism in OA remain unclear. Here, the effects and mechanisms of dexmedetomidine in OA synovial inflammation were investigated both in vivo and in vitro. We observed that dexmedetomidine stunted LPS-induced migration and invasion of FLSs and the expression of inflammatory factors by upregulating cannabinoid receptor type 2 (CB) expression. Surprisingly, the application of AM630 (CB antagonist) reversed this therapeutic effect. The results of the animal experiments showed that dexmedetomidine reduced synovial inflammation and increased the pain threshold in an OA rat model. These preliminary results imply that dexmedetomidine may be an effective compound for OA treatment.