Purpose The prefrontal cortex [PFC] is crucial in controlling food-related impulses. Functional near-infrared spectroscopy [fNIRS] represents a wearable functional neuroimaging technology for measuring PFC activation in real life. Aims of the study were to examine PFC activation in fasting conditions and after an oral glucose tolerance test [OGTT] in resting- state [R], cognitive tasks [Ts] conditions and explore the PFC activation relationship with insulin sensitivity index [ISI] in youths with obesity. Methods 28 patients’ cross-sectional study [age 7—15 y]. ISI was quantified by Matsuda’s Index and PFC activation as oxygenated [O2Hb, mol/L] and total [tHb, mol/L] hemoglobin concentration changes, in fasting and during the first 60 min of the OGTT; in resting-state condition and during cognitive tasks [Ts: Verbal Fluency, Digit Span, Non-Verbal Stroop] administered before [Fasting-Ts], and 15 min after OGTT [OGTT-Ts]. 15 min OGTT-R was divided into 5 time periods [P1-P2-P3-P4-P5], and cognitive tasks [OGTT-Ts] were then administered again. Results Dorsolateral PFC [DLPFC] and right frontal pole were over-activated in OGTT compared to the fasting state. Significant differences [p textless 0.005, false discovery rate corrected] were observed: P2 [O2Hb Left DLPFC Fasting-R: 1.4710–6 vs OGTT-R: 4.1310–6 mol/L], P3 [tHb Right DLPFC Fasting-R: 1.1510–6 vs OGTT-R: 3.3610–6 mol/L], and P5 [ O2Hb Left DLPFC Fasting-R: 1.4710–6 vs OGTT-R: 4.3410–6 mol/L, tHb Right DLPFC Fasting-R: 1.1510–6 vs OGTT-R: 3.0710–6 mol/L]. The change of left DLPFC activity correlated significantly with ISI [r = 0.61, p textless 0.001]. Conclusion fNIRS enabled the non-invasive examination of the PFC hemodynamic response associated with participants’ insulin sensitivity in an ecological context. Bilateral DLPFC activation following OGTT in youths with obesity was associated with peripheral ISI. This association suggests that peripheral insulin sensitivity might reflect the PFC’s ability to control food-related behaviours.