Methamphetamine (MA) is a psychostimulant with a high potential for abuse and neurotoxic effects, primarily affecting the brain's monoamine neurotransmitter systems. Recently, its overdose or concurrent use with alcohol (EtOH) has been associated with a notable increase in hospitalizations and mortality. In this study, we examined locomotor behavior, as well as metabolic and pharmacokinetic interactions, following the co-administration of low, medium, and high doses of MA (hydrochloride salt, 1, 4, and 10 mg/kg, intraperitoneal) and EtOH (2 g/kg, 30%, v/v, intraperitoneal) in rats. Locomotion was reduced while the total incidence of stereotypy was enhanced in dose-dependent manner with MA. Remarkably, co-administration of EtOH significantly decreased locomotion at the low dose of MA, while stereotypy was delayed but intensified at the medium and high doses. Importantly, urinary and plasma concentrations of MA and its active metabolite, amphetamine (AM), increased significantly, whereas those of 4-hydroxy MA decreased with EtOH exposure. The pharmacokinetic analysis results indicated that the co-administration of MA and EtOH increased the Cmax, half-life, and area under the curve (AUC) of MA, while the volume of distribution and total clearance decreased compared to MA administration alone. Comparison of the metabolite-to-parent drug AUC ratios showed that the conversion of MA to AM was enhanced with EtOH administration. Consequently, the concurrent use of MA and EtOH exacerbated the metabolism and elimination of MA, intensifying its neurotoxic effects. These findings will aid in the clinical interpretation of MA intoxication.