Despite growing evidence linking diabetes to brain dysfunction, the specific long-term effects of type 1 (T1D) and type 2 diabetes (T2D) on hippocampal and prefrontal cortex (PFC) function remain poorly characterized. This study aimed to provide a comprehensive comparison of the chronic neurobiological, cognitive, and behavioral consequences of sustained hyperglycemia in experimental models of T1D and T2D. By integrating behavioral assessments with biochemical and neurochemical analyses, we sought to delineate diabetes type-specific patterns of dysfunction within the hippocampus and PFC. Adult rats were randomly divided into three groups: Sham, T1D, and T2D. T1D was induced by a single intraperitoneal injection of streptozotocin (STZ), while T2D was established via nicotinamide (NA) administration 15 minutes prior to STZ injection. Behavioral and cognitive assessments were conducted during the final phase of the 100-day experimental period. Following testing, blood samples were collected for biochemical analyses, and the hippocampus and PFC were dissected to assess oxidative stress markers, inflammatory mediators, acetylcholinesterase (AChE) activity, BDNF levels, and Na⁺/K⁺-ATPase activity. Histological examinations using Nissl staining were performed to evaluate neuronal integrity. After 100 days of hyperglycemia, both diabetic models exhibited significant functional and structural alterations in the hippocampus and PFC. T2D was associated with pronounced oxidative stress and inflammation, correlating with anxiety- and depression-like behaviors (P < 0.05). Conversely, T1D rats displayed more extensive cognitive impairment, along with severe neurochemical and structural disruptions, including marked BDNF depletion, significant Na⁺/K⁺-ATPase reduction, and elevated AChE activity (P < 0.05), indicative of greater neuronal stress and degeneration. These findings underscore diabetic encephalopathy as a multifactorial disorder involving interrelated deficits in neurotrophic support, metabolic regulation, and neurotransmitter balance. While T2D is characterized predominantly by oxidative and inflammatory stress, T1D exerts more profound neurochemical and structural damage within the hippocampus and prefrontal cortex.