Methamphetamine (METH) is a highly addictive drug that might induce neurotoxicity. Clinical trials have reported that modafinil, a wake-promoting agent used to treat sleep disorders, may have some efficacy for the treatment of psychostimulant addiction. In this study we tested possible neuroprotective effects of modafinil after toxic METH administration in mice. We evaluated the effect of modafinil (two injections of either 90 or 180 mg/kg) and METH binge (3 × 7 mg/kg i.p. injections, 3-h apart) coadministration on DA striatal content, TH immunoreactivity in striatal areas and spontaneous locomotor activity. We also investigated acute locomotor activity and stereotypy profile in mice treated with a single METH dose (2 and 7 mg/kg) pretreated with modafinil (90 and 180 mg/kg). We found that mice treated with a METH binge showed a marked decrease in DA and dopaminergic metabolites as well as lower levels of TH immunoreactivity in the dorsal striatum. Pretreatment with modafinil (both 90 and 180 mg/kg) attenuated these effects but did not prevent METH induced decrease in locomotion. We also found that groups that received the combination of both modafinil and single dose METH showed a decrease in total distance traveled in an open field compared with METH groups. We observed an increment in the time mice expended doing stereotypic movements (continuous sniffing) in the group that received the combination of both METH and modafinil (i.e., decreasing locomotion). Our results suggest a possible protective role of modafinil against METH acute striatal toxicity.