Background Electrical stimulation of skin afferents can induce somatosensory plasticity in humans. Nevertheless, it is unknown if this is possible to do through percutaneous stimulation of a peripheral nerve, which will allow for regional anaesthesia interventions. Furthermore, potentiation protocols applied over mainly non‐nociceptive fibres inhibit nociception in rodents, but this has not been tested in humans. Objective To determine whether a protocol aiming to depress the nociceptive circuit and another aiming to potentiate non‐nociceptive circuits produce regional hypoalgesia and changes in motor function, applied through percutaneous peripheral nerve stimulation (pPNS), and to assess which of them is more promising for pain relief, immediately and 24 h after the intervention. Methods PT‐cLF protocol aims to depress the nociceptive pathway through Pain Threshold, continuous Low Frequency stimulation and ST‐bHF aims to produce potentiation of the non‐nociceptive pathway, through Sensory Threshold burst stimulation at High Frequency. All subjects (n = 29) went through both protocols and a control condition in a randomized and blinded crossover design. Results Compared to control, ST‐bHF induced distal hypoalgesia, towards electrical (p = 0.04) and mechanical stimuli (p = 0.02) and produced mechanical hypoesthesia (p = 0.02). Contrarily, hypoalgesia was not observed after PT‐cLF (p > 0.05) but increased electrical motor threshold (p = 0.04), reduced motor recruitment (p = 0.03), and the subjects reported feeling reduced strength (p < 0.01). Conclusion This works provides evidence that is possible to induce antinociceptive plasticity in a wide territory using pPNS. Moreover, it demonstrates for the first time in humans that a protocol aiming to produce long‐term potentiation applied predominantly over non‐nociceptive afferents induces hypoesthesia and hypoalgesia.