BACKGROUND: Transcutaneous peripheral nerve electrical stimulation using high-frequency pulse clusters has been shown to relieve muscle fatigue, though its efficacy remains limited. Furthermore, this approach tends to exacerbate pain during stimulation, which constrains its clinical applications. This paper proposed a novel stimulation waveform to reduce muscle fatigue and the discomfort associated with high-frequency electrical stimulation, and compares it with previously reported high-frequency pulsed cluster stimulation. METHODS: We evaluated our waveform experimentally and through model simulations. During the experiment, two distinct high-frequency narrow pulse clusters were applied to the proximal segment of the median/ulnar nerve bundles: asymmetric random (aSymR) and previously reported symmetric (Sym) stimulation, both with a carrier frequency of 10 kHz. The two stimulation modes aimed to elicit the same contraction level and were maintained for 5 min to induce muscle fatigue. Finger force, high-density electromyographic (EMG) signals of the flexor muscles and the pain score were recorded. In addition, we developed a finite element model of the upper arm and a motor fiber model to simulate motor axon activation of the peripheral nerve induced by the two electrical stimulation modes. RESULTS: Compared with the Sym stimulation, the aSymR stimulation resulted in less pain and a significant reduction of muscle fatigue rate, which was characterized by slower force decay rate, less absolute force decay, greater plateau force, and ultimately greater force output. In addition, the simulation results showed that the delay for different fibers to reach the threshold was increased by the aSymR mode. Consistent with this, the experiment study showed that the EMG amplitude under the aSymR stimulation condition was smaller before fatigue onset, indicating the less synchronized activation of different muscle fibers. CONCLUSIONS: Compared with the Sym stimulation, the aSymR stimulation can significantly relieve muscle fatigue possibly by reducing the synchronous activation across different fibers. This proposed aSymR stimulation mode not only reduces fatigue but also relieves pain, potentially contributing to the wide application of electrical stimulation in motor function rehabilitation for people with stroke. TRIAL REGISTRATION: Ethics committee of the Medical College of Xi'an Jiaotong University, 2021 - 1550. Registered 4 November 2021.