<p>Type 2 diabetes mellitus (T2DM), which occurs due to frequent consumption of a high-fat diet (HFD), is recognized as a significant risk factor for progressive cognitive decline. The present study investigates the potential neuroprotective effects of fisetin, alone and in combination with <i>Lactobacillus</i>, in an HFD-STZ-induced T2DM rat model. Diabetes was induced by feeding HFD and a single dose of STZ injection of 45&#xa0;mg/kg intraperitoneally in albino Wistar rats. After confirmation of the diabetic state, rats were administered fisetin (25, 50&#xa0;mg/kg) orally, in combination with <i>Lactobacillus</i> at 1.5 × 10⁹ CFU/mL. Cognition and memory were analyzed by NORT, MWM, EPM, biochemical markers, neurotransmitters, and molecular (NF-κB via immunohistochemistry) assessments, along with histopathological analysis of tissues, were performed. Fisetin, alone and in combination with <i>Lactobacillus</i>, treatment restored cognitive deficits and glucose level, as well as attenuated lipid profile, biochemical, and neurochemical abnormalities in rats (<i>p</i> &lt; 0.05 vs. STZ-HFD group). Further, the combination of fisetin (50&#xa0;mg/kg/<i>p.o.)</i> with <i>Lactobacillus (</i>1.5 × 10⁹ CFU/mL) significantly achieved a protective effect as compared to treatment with fisetin alone in diabetic rats (<i>p</i> &lt; 0.05 vs. STZ-HFD Fisetin 25 and 50&#xa0;mg/kg/ <i>p.o.</i> group). Results of the study revealed that the combination of fisetin with <i>Lactobacillus</i> exhibits impressive anti-oxidant, modulates neurotransmitter levels, and suppresses the NF-κB pathway, promising a strategy for treating diabetes-associated cognitive problems.</p> Graphical abstract <p></p>