We determined if interval exercise plus a low‐calorie diet (LCD + INT) increases endothelial function more than an energy‐matched LCD. Obese women (47.2 ± 2.6y, 37.5 ± 1.3kg/m 2) were randomized to 13 days of a LCD ( n = 12; mixed meals of ~ 1200kcal/d) or LCD + INT ( n = 13; 12 supervised 60‐min INT bouts of 3 min at 90% and 50% HR peak). LCD + INT subjects received 350kcal postexercise to equate energy availability with LCD. Fitness (VO 2peak) and body composition (BodPod) were determined and a 120 min, 75 g oral glucose tolerance test was performed to examine fasting and postprandial flow‐mediated dilation (FMD, endothelial function), respiratory exchange ratio (RER) via indirect calorimetry as well as glucose and insulin incremental area under the curve (iAUC 120min). LCD + INT increased VO 2peak ( P = 0.02) compared with LCD, and both treatments decreased fat mass ( P < 0.001) and insulin iAUC 120min ( P = 0.03). There was no overall treatment effect on fasting or iAUC 120min FMD. However, in participants who increased fasting endothelial function after each treatment (Δ > 50%; LCD n = 5, LCD + INT n = 7), LCD + INT increased fasted ( P = 0.005) and decreased iAUC 120min ( P = 0.003) FMD compared with LCD. Enhanced fitness correlated with increased fasting FMD ( r = 0.43, P = 0.03) and diminished FMD iAUC 120min ( r = −0.44, P = 0.03). Decreased FMD iAUC 120min correlated with reduced glucose iAUC 120min ( r = 0.64, P = 0.001) as well as increased 60‐min RER ( r = −0.42, P = 0.04). Low baseline fasting and iAUC 120min FMD was also linked to enhanced fasting and iAUC 120min FMD post‐treatment ( r = −0.71, P < 0.001; r = −0.89, P < 0.001, respectively). In conclusion, increasing fitness via INT may increase the effect of LCD on lowering cardiovascular disease risk in obese women.