Transcutaneous electrical nerve stimulation (TENS), as a non-pharmacological and non-invasive analgesic therapy with low-cost, has been widely used to relieve pain in various clinical applications, by delivering current pulses to the skin area to activate the peripheral nerve fibers. Nevertheless, analgesia induced by TENS varied in the clinical practice, which could be caused by the fact that TENS with different stimulus parameters has different biological mechanisms in relieving pain. Therefore, to advance our understanding of TENS in various basic and clinical studies, we discussed (1) neurophysiological and biochemical mechanisms of TENS-induced analgesia; (2) relevant factors that may influence analgesic effects of TENS from the perspectives of stimulus parameters, including stimulated position, pulse parameters (current intensity, frequency, and pulse width), stimulus duration and used times in each day; and (3) applications of TENS in relieving clinical pain, including post-operative pain, chronic low back pain and labor pain. Finally, we propose that TENS may involve multiple and complex psychological neurophysiological mechanisms, and suggest that different analgesic effects of TENS with different stimulus parameters should be taken into consideration in clinical applications. In addition, to optimize analgesic effect, we recommend that individual-based TENS stimulation parameters should be designed by considering individual differences among patients, e.g., adaptively adjusting the stimulation parameters based on the dynamic ratings of patients' pain.