It aimed to observe the effects of TongDu TiaoShen (TDTS) electroacupuncture (EA) on the analgesia and central system of knee osteoarthritis (KOA) rats and explore its mechanism. SD rats were rolled into the blank group, model group (KOA), control group (duloxetine 500 mg/kg/d, Ctrl), conventional EA group, and TDTS-EA group. Radiometric pain measurements and the Lequesne MG scale were used to evaluate the behavioral performance of the rats. Dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), β-endorphin (β-EP), and leucine-enkephalin (L-ENK) were detected in the midbrain and spinal cord of lumbar enlargement. Interleukin (IL)-1β protein expression was detected by Western blot. The incubation period of thermal pain and foot contraction was decreased in the KOA group versus blank group, the Lequesne MG score was increased, DA, NE, 5-HT, β-EP, and L-ENK in the midbrain and spinal cord were increased, and synovial tissue IL-1β protein expression was increased (P < 0.05). EA group and TDTS-EA group had an increased incubation period of thermal pain contraction, decreased Lequesne MG score, decreased DA, NE, etc. In the midbrain, increased 5-HT and NE in the spinal cord, and decreased IL-1β in the synovial tissue versus KOA group (P < 0.05). The Lequesne MG score and midbrain DA, NE, 5-HT, β-EP, and synovial tissue IL-1β expression were decreased in TDTS-EA group versus EA group (P < 0.05). EA can effectively improve the behavioral score of KOA and participate in central analgesia by regulating central DA, NE, 5-HT, β-EP, and L-ENK.© 2023 The Authors.