Objectives Sestrins (SESNs) and sirtuins (SIRTs) are antioxidant and antiapoptotic genes and crucial mediators for lysosomal autophagy regulation that play a pivotal role in the Alzheimer's disease (AD). Recently, statins have been linked to the reduced prevalence of AD in statin-prescribed populations yet molecular basis for the neuroprotective action of statins is still under debate. Methods This study was undertaken whether A beta-induced changes of SESN2 and SIRT1 protein expression, autophagy marker LC3II and lysosomal enzyme TPP1 affected by atorvastatin (Western blot) and its possible role in A beta neurotoxicity (ELISA). Key findings/results We showed that SESN2 and LC3II expressions were elevated, whereas SIRT1 and TPP1 expressions were decreased in the A beta(1-42)-exposed human neuroblastoma cells (SH-SY5Y). Co-administration of atorvastatin with A beta(1-42) compensates SESN2 increase and recovers SIRT1 decline by reducing oxidative stress, decreasing SESN2 expression and increasing SIRT1 expression by its neuroprotective action. Atorvastatin induced LC3II but not TPP1 level in the A beta(1-42)-exposed cells suggested that atorvastatin is effective in the formation of autophagosome but not on the expression of the specific lysosomal enzyme TPP1. Discussion and conclusion Together, these results indicate that atorvastatin induced SESN2, SIRT1 and LC3II levels play a protective role against A beta(1-42) neurotoxicity.