Methamphetamine (METH) is a highly addictive psychostimulant, and its abuse results in severe neurotoxicity and drug addiction. However, the exact molecular mechanism through which METH causes this damage is incompletely understood. In the current study, we investigated whether ferroptosis-associated changes, an iron-dependent form of cell death involving lipid peroxidation and glutathione peroxidase-4 (GPX-4) depletion, contribute to METH-induced brain damage and whether cannabidiol (CBD) pretreatment exerts a neuroprotective effect. Post-mortem prefrontal cortex brain tissue from confirmed chronic METH users and matched controls was examined for ferroptosis biomarkers. In parallel, a mouse conditioned place preference (CPP) model was used to evaluate METH-induced behavioral effects and neurochemical changes with CBD pretreatment. METH users exhibited increased iron levels, higher levels of lipid peroxidation, lower GPX-4 expression, and elevated cell death compared with control individuals. Similarly, mice repeatedly exposed to METH developed a strong place preference and exhibited increased iron levels, higher lipid peroxidation, lower GPX-4 expression, and elevated cell death. While CBD pretreatment significantly reduced the behavioral and biochemical changes induced by METH. Our findings show that chronic METH exposure induces iron-associated oxidative neurotoxicity in the prefrontal cortex, with changes consistent with ferroptosis-like cell damage, and that CBD pretreatment partially reduces these effects. This suggests that CBD has a potential preventive neuroprotective effect against METH-induced oxidative damage.