This study deals with the possible inhibitory role played by acetyl-l-carnitine (ALC) against methamphetamine (METH)-induced behavioral sensitization. Because valproate (VAL) inhibits the behavioral sensitization exerted by different psychostimulants, we investigated ALC's potential to prevent the amplification of METH-mediated psychomotor effects. We therefore evaluated the locomotor effects of VAL or ALC alone or in combination with METH after acute (day 1) as well as repeated (day 7) drug challenge. Finally, to assess the induction of behavioral sensitization, we also recorded the METH-mediated locomotor response after 7 days of drug suspension (day 15). Results showed that both VAL and ALC prevented the METH-induced sensitization. Another interesting observation was the significantly higher METH-induced hyperactivity at day 15 (after a 7-day drug-free period), indicating that behavioral sensitization developed during the washout period. Results also showed that both the acute and repeated coadministration of METH with either VAL or ALC inhibited METH-induced hyperactivity. We present different hypotheses concerning similar but also peculiar mechanisms that might underlie the preventive action of VAL and ALC. These data add to a growing body of literature that illustrates the potential of ALC in protecting against the insult of dysfunctional mitochondrial metabolism and psychostimulant-mediated neurotoxicity. By demonstrating an in vivo action against one of the most abused drugs, these results raise the possibility of beneficial effects of ALC in abuse behavior.