Aims <p>Head-to-head comparisons of neuroprotective efficacy of glucose-lowering agents remain lacking in type 2 diabetes (T2D) patients with mild cognitive impairment (MCI). Here, we investigated the effects of henagliflozin or gliclazide on brain functional alterations and cognitive changes in these patients.</p> Materials and methods <p>Twenty-four T2D patients with MCI were randomized (1:1) to receive henagliflozin or gliclazide treatment for 16 weeks. We assessed anthropometric and metabolic profiling, global and domain-specific cognitive testing, olfactory performance, and structural and functional magnetic resonance imaging (fMRI) at baseline and follow-up. The primary outcome was the between-group difference in odor-task fMRI activation at week 16.</p> Results <p>Treatment with henagliflozin for 16 weeks significantly increased odor-task fMRI activation in the left frontal white matter (Gaussian random field corrected) compared to gliclazide. Subsequent seed-based analysis revealed reduced functional connectivity to the left middle frontal gyrus, suggesting altered frontal network integration. These functional brain alterations were accompanied by significant improvements in global cognition (Montreal Cognitive Assessment [MoCA]: Δ + 2.1 vs. Δ − 0.2, <i>P</i> = 0.002) and delayed memory (Δ + 5.7 vs. Δ − 2.7, <i>P</i> = 0.012) in henagliflozin compared to gliclazide. Exploratory analyses suggested potential associations between concomitant metabolic improvements and cognitive/neuroimaging alterations, which merit further investigation.</p> Conclusions <p>Our study showed that henagliflozin enhanced frontal brain activity and improved cognition (global and domain-specific: delayed memory) in T2D patients with MCI over 16 weeks, whereas gliclazide did not. These findings highlight the potential of henagliflozin for cognitive protection in this high-risk population.</p> Registration <p>ClinicalTrials.gov (NCT06085703).</p>