Neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are multifactorial disorders which are increasing in incidence and prevalence over world without existing effective therapies. The search of new multi-target compounds are the latter therapeutically strategy to address these pathological conditions. Lichens have an important and unknown therapeutic value attributed to their unique secondary metabolites. The aim of this study is to evaluate for first time the in vitro neuroprotective activities and molecular mechanisms underlying of methanol extracts of lichens of parmelioid clade and to characterize major bioactive secondary metabolites responsible for their pharmacological actions. Of the fifteen parmelioid lichen species, our results showed that Parmotrema perlatum and Hypotrachyna formosana methanol extracts exhibited the high antioxidant activity as evidenced in ORAC, DPPH and FRAP assays. Then, SH-SY5Y cells were pretreated with methanol extracts (24 h) followed by Fenton reagent exposure (2 h). Pretreatments with these two more antioxidant methanol lichen extracts increased cell viability, reduced intracellular ROS, prevented oxidative stress biomarkers accumulation and upregulated antioxidant enzymes (CAT, SOD, GR and GPx) activity compared to Fenton reagent cells. The neuroprotective activity was much higher for H. formosana than for P. perlatum, even equal to or higher than Trolox (reference compound). Moreover, H. formosana extracts inhibited both AChE and BuChE activities in a concentration dependent manner and P. perlatum only showed concentration dependent manner activity against AChE. Finally, chemical composition analysis using TLC and HPLC methods revealed that physodic acid, lividic acid and lichexanthone are major secondary metabolites in H. formosana are and stictic acid and constictic acid are in P. perlatum. These results demonstrated that P. perlatum and specially, H. formosana, are promising multi-targeted neuroprotective agents due to their antioxidant and AChE and BuChE inhibition activities.