Osteoarthritis (OA) is a bone disease mainly treated with nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve pain. However, the exact mechanisms underlying this disease remain elusive, which creates an attractive opportunity to explore the mechanisms and provide intentional treatments for OA. In this narrative review, we selected articles discussing advancements and applications of PGE2 to OA biology and pathology and discussed how PGE2 reacts during OA-associated pain, the resulting bone structural alterations, and the potential drugs or treatments for patients with OA. We aimed to summarize the accumulating evidence suggesting that prostaglandin E2 (PGE2) plays an important role in the central sensitization of OA-related pain, elucidating the precise mechanisms underlying the pain relief effects of NSAIDs. Additionally, we interpreted the potential mechanisms by which PGE2 influences bone repair and regeneration at different stages of bone remodeling in OA progression, which raises concerns regarding the side effects of NSAIDs in bone remodeling during disease progression. Finally, we discussed the potential therapeutic strategies for different stages of OA based on available evidence. This review focused on the newly found evidence for the novel functions of PGE2 in central sensitization and bone remodeling and provides possible future directions for the treatment of OA.