Different diets have distinct impacts on glucose homoeostasis, for which insulin sensitivity (IS) after a meal (postprandial IS) is highly relevant. Postprandial IS depends upon hepatic parasympathetic activation and glutathione content elevation. We tested the hypothesis that postprandial IS is compromised in high-fat diet (HFD)-induced obesity. Sprague–Dawley rats were fed a standard diet (STD, n 10), 1-week HFD (n 9) or 4-week HFD (n 8). IS was tested in postprandial state using the rapid IS test (RIST) before and after the blockade of the parasympathetic nerves (atropine, 1 mg/kg); parasympathetic-dependent IS was obtained from the difference between control and post-atropine RIST. Fasting IS was also assessed in the STD-fed rats (n 4) and 4-week HFD-fed rats (n 3) using the RIST. Whole-body fat and regional fat pads were heavier in the 1-week HFD-fed rats (79·8 (se 7·9) and 23·7 (se 1·0) g, respectively) or 4-week HFD-fed rats (106·5 (se 6·1) and 30·1 (se 1·4) g, respectively) than in the STD-fed rats (32·5 (se 3·7) and 13·7 (se 1·0) g, respectively; P < 0·001). Fasted-state IS was similar between the groups studied. Postprandial IS was higher in the STD-fed rats (185·8 (se 5·6) mg glucose/kg body weight (bw)) than in both the 1-week HFD-fed rats (108·8 (se 2·9) mg glucose/kg bw; P < 0·001) and 4-week HFD-fed rats (69·3 (se 2·6) mg glucose/kg bw; P < 0·001). Parasympathetic-dependent IS was impaired in both HFD-fed groups (STD, 108·9 (se 3·9) mg glucose/kg bw; 1-week HFD, 38·6 (se 4·2) mg glucose/kg bw; 4-week HFD, 5·4 (se 1·7) mg glucose/kg bw; P < 0·001). Total (postprandial) and parasympathetic-dependent IS correlated negatively with whole-body fat (R² 0·81 and 0·87) and regional adiposity (R² 0·85 and 0·79). In conclusion, fat accumulation induced by HFD is associated with postprandial insulin resistance, but not with fasting insulin resistance. HFD-associated postprandial insulin resistance is largely mediated by impairment of parasympathetic-dependent insulin action, which correlates with adiposity.