Diabetic peripheral neuropathy (DPN), as one of the most prevalent complications of diabetes, leads to significant pain and financial burden to patients. Currently, there was no effective treatment for DPN since the glucose control was just a prevention and the drug therapy only relieved the DPN pain. As a non-invasive physical therapy, low-intensity pulsed ultrasound (LIPUS) is utilized in the musculoskeletal and nerve injuries therapy. Studies revealed that LIPUS could regenerate nerves by the mechanical stimulation via oxidative stress pathway, which was thought as the important factor for DPN, and might have potential in the DPN therapy. This study aimed to identify a new therapeutic strategy for DPN using LIPUS. We analyzed the therapy effect and explored the therapeutic mechanism of LIPUS on DPN in mice. This study involved animal experiments and C57BL/6J mice were randomly assigned to DPN model and Sham groups. The DPN model group was fed a high-fat chow diet and injected with streptozotocin (STZ) for 3 consecutive days (40 mg/kg/d), whereas the Sham group was fed a normal diet and injected with an equal volume of sodium citrate buffer. After the DPN model confirmed with the 84-day modeling process, the DPN mice were randomly allocated into the DPN group and the LIPUS group. The LIPUS group underwent ultrasound treatments with a center frequency of 1 MHz, a duty cycle of 20 %, and a spatial average temporal average intensity (I