Abstract Objective Transcutaneous electrical nerve stimulation (TENS) based on wrist-ankle acupuncture has been shown to relieve pain levels in patients with myofascial pain syndrome (MPS). However, its efficacy is highly subjective. The purpose of this study was to evaluate the feasibility and effectiveness of TENS based on wrist-ankle acupuncture for pain management in patients with MPS from the perspective of cerebral cortex hemodynamics. Design, setting, participants and interventions We designed a double-blind, randomized, controlled clinical trial. Thirty-one male patients with MPS were randomly assigned to two parallel groups. The experimental group (n = 16) received TENS based on wrist-ankle acupuncture for analgesic treatment, while the control group (n = 15) did not. The pain was induced by mechanically pressurized at acupoint Jianjing. The multichannel functional near-infrared spectroscopy (fNIRS) equipment was utilized for measuring oxyhemoglobin (HbO) levels in the cerebral cortex during the tasks. Results After the intervention, visual analog scale (VAS), the activation degree and activation area of pain perception cortices were significantly reduced in the experimental group compared to the baseline values (P<0.05). Particularly, Frontopolar Area (FPA), and Dorsolateral Prefrontal Cortex (DLPFC) are highly involved in the pain process and pain modulation. Conclusion Compared to no intervention, TENS based on wrist-ankle acupuncture can be effective in relieving pain in patients with MPS in terms of cerebral cortical hemodynamics. However, further studies are necessary to quantify the analgesic effect in terms of cerebral hemodynamics and brain activation. Trial registration The study was registered in the Chinese Trial Registry (No. ChiCTR2200056394).