Our present study focused on the evaluation of the antioxidant, anti-inflammatory, and neuroprotective potential of BC and CBD in HG-promoted toxicity and STZ-induced diabetic neuropathy through alterations in AMPK and SIRT1 activation, which may also be connected to altered, PGC-1α-mediated, mitochondrial biogenesis, PARKIN–PINK1–p62-mediated autophagy, antioxidant effects through Nrf2 overactivation, and anti-inflammatory effects through the NFkB and NLRP3 inflammasome. This evidence concerns the gene PPARGC1A and diabetic neuropathy.