Hipericum perforatum is a well-known herbal for its antidepressant property. Recently, it has been shown to have nootropic effects against neurodegenerative disorders. The aim of the present study was to evaluate the protective role of chronic administration of two standardized extract of Hypericum perforatum SHP1 rich in hyperforin (6%) and SHP2 extract poor in hyperforin (0.2%) on the neurodegeneration induced by chronic administration of rotenone in rats. Quercetin in liposomes, one active constituent, was tested in the same experimental conditions. The animals received pretreatments with SHP1 (4 mg/Kg, ip), SHP2 (4 mg/Kg, ip) or quercetin liposomes (25 and 100 mg/kg, ip) 60 min before of rotenone injection (2.5 mg/kg) for 45 days. Pretreatment of the animals with SHP1 and SHP2 efficiently halted deleterious toxic effects of rotenone, revealing normalization of catalepsy in addition to amelioration of neurochemical parameters. Also, SHP1 reduced neuronal damage, diminishing substantia nigra dopaminergic cell death caused by the pesticide, indicating benefit of neuroprotective therapy. In general, the SHP1 was more active than SHP2. In addition, SHP1 inhibited the apoptotic cascade by decreasing Bax levels. The results presented here indicate that mainly hyperforin and quercetin, may be involved in the neuroprotective action of Hypericum standardized extracts. Combination of dietary antioxidants could provide better therapeutic advantage for the management of Parkinson, and possibly other neurodegenerative disorders. Therefore H. perforatum standardized extract enriched in hyperforin, could be a better alternative for depressed elderly patients with degenerative disorders exhibiting elevated oxidative stress status.