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Despite increasing evidence, the specific long-term effects of type 1 diabetes (T1D) and type 2 diabetes (T2D) on the functions of the hippocampus and prefrontal cortex (PFC) remain poorly understood. This study aimed to provide a comprehensive comparison of the chronic neurobiological, cognitive, and behavioral consequences of prolonged hyperglycemia in experimental models of T1D and T2D. By combining behavioral assessments with biochemical and neurochemical analyses, the study sought to identify diabetes type-specific patterns of dysfunction within the hippocampus and PFC. Adult rats were randomly assigned to three groups: Sham, T1D, and T2D. T1D was induced by a single intraperitoneal injection of streptozotocin (STZ), while T2D was established by administering nicotinamide (NA) 15 min prior to STZ injection. Behavioral assessments and Cognitive functions were conducted during the final phase of the experimental period. Following behavioral testing, blood samples were collected for biochemical analyses. The PFC and hippocampus were dissected for evaluation of oxidative stress markers, inflammatory mediators, acetylcholinesterase (AChE) activity, BDNF levels, and Na⁺/K⁺-ATPase activity. Additionally, a histological examination of these brain regions was performed to assess neuronal integrity using Nissl staining. After 100 days of hyperglycemia, both T1D and T2D rats exhibited significant functional and structural alterations in the hippocampus and PFC. T2D was significantly associated with pronounced oxidative stress and inflammatory responses, related with anxiety- and depression-like behaviors (P < 0.05). In contrast, T1D induced more extensive cognitive decline, neurochemical and structural disruption, including marked BDNF depletion, significant Na⁺/K⁺-ATPase reduction, and elevated AChE activity (P < 0.05), suggesting greater neuronal stress and degeneration compared to T2D. These findings highlight diabetic encephalopathy as a multifactorial disorder involving concurrent impairments in neurotrophic support, metabolic regulation, and neurotransmitter balance, with T2D characterized by greater oxidative stress and inflammation, and T1D exhibiting more severe neurochemical and structural damage.