Transcranial focused ultrasound (tFUS) is an emerging noninvasive neuromodulation technology that has shown great potential in pain modulation. This review systematically elucidates the multilevel biological mechanisms of tFUS neuromodulation, from network-wide effects to cellular and molecular processes, as well as broader systemic influences. Preliminary animal pain model studies have revealed tFUS's ability to improve pain behavioral indicators and modulate neural circuit activity under pathological conditions. A small number of clinical studies also suggest that tFUS may have certain benefits in improving symptom experience and emotional state in chronic pain patients. However, current research generally has limitations such as small sample sizes and short follow-up periods. More high-quality studies are needed to verify the long-term effects and safety of tFUS pain treatment. Overcoming these limitations and advancing large-scale clinical translational research will help fully exploit the application potential of tFUS in precision pain medicine and provide new treatment options for pain relief.