Cognitive decline is a common complication of diabetes, and is inadequately addressed by current treatments. This study examined the effects of selenium nanoparticles (SeNPs) and high-intensity interval training (HIIT) on cognitive function and neuroprotection in diabetic rats. Male Wistar rats (n = 31) were induced with diabetes and assigned to five groups entered into 8 weeks intervention: control (CO), control which receive placebo (PCO), SeNPs treatment (0.1 mg/kg) (SeNPs), HIIT (HIIT), and combined SeNPs with HIIT (SeNPs + HIIT). Cognitive function was assessed using the Morris water maze test. Hippocampal tissues were analysed for cell viability, gene expression of BDNF, GLUT4, and Irisin receptor, as well as serum protein levels of Irisin and hippocampal BDNF protein level. Results showed that all treatment groups had a significant effect on learning, memory, cell viability, GLUT4, BDNF and irisin (P < 0.03). Serum Irisin was higher in HIIT and SeNPs + HIIT groups (P < 0.0001), also SeNPs and SeNPs + HIIT groups showed increased GLUT4 expression (P < 0.03). SeNPs + HIIT groups had the significant effect on BDNF both gene and protein compared to the all control (CO, PCO) groups (P < 0.01). These findings suggest that combining SeNPs and HIIT may mitigate cognitive decline and promote neuroprotection in diabetes via modulation of Irisin and BDNF pathways and improved glucose metabolism. While synergy is suggested, mechanistic confirmation requires further study. Translational potential exists, but clinical validation is needed due to species differences. Limitations include unmonitored confounders, sample size, and lack of mechanistic validation, highlighting the need for future research.