INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a widespread metabolic illness that compromises cognitive function by inducing inflammation and oxidative damage. Diabetes mellitus is treated with many types of medications, including tirzepatide (TZP) and pioglitazone (PIO), which have also been shown to enhance cognitive deficits associated with the condition. This study intends to investigate the neuroprotective effects of TZP and PIO on type 2 diabetic mellitus (T2DM) via mitigating neuroinflammation and oxidative stress, along with enhancing cognitive impairment in rats as models with T2DM. METHODS: A total of six distinct groups of sixty albino rat males (n = 10) were allocated at random: Saline, TZP, PIO, T2DM, T2DM+TZP, and T2DM+PIO. Intramuscular doses of streptozotocin (50 mg/kg) and nicotinamide (120 mg/kg) precipitated T2DM. The TZP and PIO therapies persisted for a duration of 15 days. The survival percentage, body weight, behavioral assessments (Y-maze, novel object recognition (NOR)), glucose concentrations, inflammatory mediators tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin-1 beta (IL-1β), as well as oxidative stress biomarkers superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), and lipid peroxidation were evaluated following the conclusion of the treatments. RESULTS: The results demonstrate that diabetes decreased survival rates, body weight, cognitive function, increased glucose levels, neuroinflammation, and oxidative stress. The TZP and PIO increased survival rates and cognitive function as well as decreased glucose levels, neuroinflammation, and oxidative stress in diabetic rats, with PIO demonstrating a more pronounced effect on neuroinflammation and oxidative stress, contrasted with TZP. DISCUSSION: This study concluded that TZP and PIO enhanced cognitive impairment in diabetic rats, with PIO demonstrating superior efficacy in contrast to TZP.