Adolescents and females experience worse outcomes of drug use compared to adults and males. This could result from age- and sex-specific consequences of drug exposure on brain function and cognitive behavior. In the current study, we examined whether a history of intravenous methamphetamine (METH) self-administration impacted cognitive flexibility and 5-HT2CR localization in the orbitofrontal cortex (OFC) in an age- and sex-dependent manner. Strategy shifting was assessed in male and female Sprague-Dawley rats that had self-administered METH (0.08 mg/kg/inf) or received non-contingent infusions of saline during periadolescence or young adulthood. After all rats reached adulthood, they were tested in an operant strategy shifting task and their brains were subsequently analyzed using immunofluorescence to quantify co-localization of 5-HT2C receptors with parvalbumin interneurons in the OFC. We found that adolescent-onset females were the only group impaired during discrimination and reversal learning, but they did not exhibit changes in localization of 5-HT2C receptors. In contrast, adult-onset males exhibited a significant increase in co-localization of 5-HT2C receptors within parvalbumin interneurons in the left hemisphere of the OFC. These studies reveal that age and sex differences in drug-induced deficits in reversal learning and 5-HT2CR co-localization with parvalbumin interneurons are dissociable and can manifest independently. In addition, these data highlight the potential for certain treatment approaches to be more suitable in some populations compared to others, such as alleviating drug-induced cognitive deficits as a focus for treatment in adolescent females.