Polydrug abuse is a major problem around the world. Methamphetamine (MA) and alcohol (AL) are two abused drugs which are frequently used together. Chronic abuse of either MA or AL causes oxidative stress in the brain and is associated with impairments in cognitive functions including various aspects of memory and learning. The present study examined the effect of escalating dose, multiple binge MA regimen, AL and MA-AL combination on spatial memory and the induction of oxidative stress in the hippocampus. Adult male Wistar rats were exposed to ethanol, an escalating dose of MA either individually or in combination for 28 consecutive days. In order to examine the short- and long-term effects of chronic exposure to the drugs, each group was then subdivided into two further groups. Thereafter, spatial memory was tested using a Morris water maze, either one day or 14 days after the drugs were withdrawn. At the end of the behavioral testing, oxidative stress markers including Superoxide Dismutase (SOD), Glutathione Peroxidase (GPX), Catalase (CAT), and Malondialdehyde (MDA) were measured. Our results showed that MA, but not AL, impaired spatial memory. Although AL alone had no effect, it exacerbated the impairment due to MA when the drugs were co-administered. In addition, while both drugs significantly induced oxidative stress in the hippocampus when given alone, co-administration of these drugs resulted in a greater oxidative stress and an impairment of the antioxidant enzyme glutathione peroxidase in rat hippocampus. Taken together, this study demonstrates that MA in combination with AL has synergistic effects on increased oxidative stress in the hippocampus, as well as spatial memory impairment.