Exposure to aluminum chloride (AlCl₃) induces progressive multiregional neurodegeneration in animal models by promoting oxidative stress and neuroinflammation. The current study was designed to assess the potential efficacy of the natural antioxidants celastrol and thymoquinone (TQ) for alleviating AlCl₃-induced psychomotor abnormalities and oxidative-inflammatory burden in male albino rats. Four treatment groups were compared: (i) a vehicle control group, (ii) a AlCL₃ group receiving daily intraperitoneal (i.p.) injection of AlCl₃ (10 mg/kg) for 6 weeks, (iii) a AlCl₃ plus TQ (10 mg/kg, i.p.) cotreatment group, and (iv) a AlCl₃ plus celastrol (1 mg/kg, i.p.) cotreatment group. Open-field, rotarod, and forced swimming tests were conducted to assess locomotor activity, motor coordination, anxiety-like behavior, and depressive-like behavior. Acetylcholine (ACh), dopamine, and serotonin levels were measured in brain homogenates. Malondialdehyde (MDA), total antioxidant capacity (TAC), and catalase activity were measured as oxidative stress markers, while tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6) expression levels were measured as inflammatory markers. Brain derived neurotrophic factor (BDNF) mRNA was measured as an index for the endogenous neuroprotective response. Daily AlCl₃ injection reduced free ambulation, impaired motor coordination, promoted anxiety- and depression-like behaviors, reduced whole-brain ACh, dopamine, and serotonin concentrations, increased MDA accumulation, reduced TAC, elevated TNF-α and IL-6, and suppressed BDNF mRNA expression. All of these effects were significantly reversed by TQ or celastrol cotreatment. Thus, TQ and celastrol may be promising treatments for AlCl₃-induced neurotoxicity as well as neurodegenerative diseases involving oxidative stress and neuroinflammation.