Diabetic sensorimotor polyneuropathy (DSPN) is the most prevalent complication of diabetes, affecting nearly half of all persons with diabetes. It is characterized by nerve degeneration, progressive sensory loss and pain, with increased risk of ulceration and amputation. Despite its high prevalence, disease-modifying treatments for DSPN do not exist. Mitochondrial dysfunction and Ca dyshomeostasis are key contributors to the pathophysiology of DSPN, disrupting neuronal energy homeostasis and initiating axonal degeneration. Recent findings have demonstrated that antagonism of the muscarinic acetylcholine type 1 receptor (MR) promotes restoration of mitochondrial function and axon repair in various neuropathies, including DSPN, chemotherapy-induced peripheral neuropathy (CIPN) and HIV-associated neuropathy. Pirenzepine, a selective MR antagonist with a well-established safety profile, is currently under clinical investigation for its potential to reverse neuropathy. The transient receptor potential melastatin-3 (TRPM3) channel, a Ca-permeable ion channel, has recently emerged as a downstream effector of G protein-coupled receptor (GPCR) pathways, including MR. TRPM3 activation enhanced mitochondrial Ca uptake and bioenergetics, promoting axonal sprouting. This review highlights mitochondrial and Ca signaling imbalances in DSPN and presents MR antagonism and TRPM3 activation as promising neuro-regenerative strategies that shift treatment from symptom control to nerve restoration in diabetic and other peripheral neuropathies.