Hormesis refers to a dose-response relationship that is generally characterized as a biphasic dose response, induces an adaptive beneficial effect on a cell or organism at low doses but inhibits at high doses. Recently, the hormesis concept has been receiving increasing attention in the field of neural research, indicating that improving cellular adaptive ability provides a new idea and method for the prevention and treatment of neurological diseases. A class of useful stressors could markedly increase the neuronal resistance to more drastic stress, which is defined as neurohormesis. Here we reported that natural compound Berberine, PTS and anticancer drugs can induced an obvious hormetic response in rat pheochromocytoma PC12 cells. Moreover we studied their neuroprotective effects in vitro and in vivo. MTT assay showed that the compounds stimulated the cell growth of PC12 cell and exhibited potent neuroprotective effects against injury induced by 6-OHDA and H2O2. TUNEL staining further confirmed that pretreatment of BBR and PTS significantly reduced the cell apoptosis in 6-OHDA-induced injury. Western blot analysis demonstrated that antioxidant and anti-apoptosis proteins were up regulated by low doses of BBR, PTS and CPT, as evidenced by increased levels of p-PI3K, p-AKT, p-mTOR, AMPK, Sir1, Sir3, Nrf2, and HO-1. And inhibition of PI3K by LY294002 abolished the growth promoting effect of CPT and BBR. These results suggest that the hormetic and neuroprotective effects of CPT and BBR at low doses on PC12 cells were attributable, at least partially, to up-regulated PI3K/Akt and Nrf2/HO-1 pathways. Our results provide new ideas for the investigation of neuroprotective mechanisms and drug screening.