Hippocampal dysfunction associated with type 2 diabetes mellitus (T2DM), including deficits in spatial learning and memory, represent a significant challenge to overall health. Dietary interventions are considered effective therapeutic approaches for managing metabolic parameters in T2DM, with a low-carbohydrate and high-protein (LC-HP) diet being a representative example. However, the impact of an LC-HP diet on hippocampal dysfunction in T2DM remains unclear. In this study, we examined the potential role of an LC-HP diet to alleviate spatial memory impairments. C57BL/6J and ob/ob mice were assigned to either an LC-HP diet group (25.1% carbohydrate, 57.2% protein, and 17.7% fat as percentages of calories) or a control diet group (58.9% carbohydrate, 24.0% protein, and 17.1% fat as percentages of calories). After four weeks of dietary intervention, all mice underwent the Morris water maze test, followed by hippocampal mRNA expression analysis. The findings demonstrated that the LC-HP diet improved spatial memory performance in ob/ob mice. This dietary regimen mitigated the downregulation of hippocampal mRNA levels for low-density lipoprotein receptor-related protein 6 (Lrp6), IGF-1 receptor (Igf1r), and Wnt3a observed in ob/ob mice. These results suggest that modulating biochemical molecules may play a role in ameliorating memory deficits associated with T2DM through LC-HP dietary interventions, highlighting potential targets for developing nutritional strategies to address hippocampal dysfunction caused by T2DM.