Recent research has illuminated how acupuncture alleviates knee osteoarthritis (OA) symptoms by targeting key pain and inflammation pathways. A study involving rabbits with induced knee OA revealed that daily 20-minute acupuncture sessions at specific acupoints, including Neixiyan, Dubi, Xuehai, Zusanli, Hegu, and Yanglingquan, over 28 days significantly improved pain scores, joint swelling, and gait mobility compared to an untreated OA group. Notably, the research uncovered that acupuncture modulates pain and inflammation by stimulating sympathetic nerve activity and enhancing the melatonin (MLT) / cyclic adenosine monophosphate (cAMP) / protein kinase A (PKA) / cAMP response element-binding protein (CREB) signaling pathway. This resulted in upregulated melatonin-related proteins and receptors and increased expression of cAMP, PKA, and CREB, while also downregulating the inflammatory marker MMP-3. These findings not only reinforce the traditional use of these acupoints in East Asian medicine but also provide a molecular understanding of acupuncture's joint-protective and pain-relieving effects, highlighting its potential as a valuable adjunctive therapy for knee OA.