Whilst the exercise-induced myokine interleukin-6 (IL-6) plays a beneficial role in cardiac structural adaptations, its influence on exercise-induced functional cardiac outcomes remains unknown. We hypothesised that IL-6 activity is required for exercise-induced improvements in left ventricular global longitudinal strain (LV GLS). In an exploratory study 52 individuals with abdominal obesity were randomised to 12 weeks’ high-intensity exercise or no exercise in combination with IL-6 receptor inhibition (IL-6i) or placebo. LV strain and volume measurements were assessed by cardiac magnetic resonance. Exercise improved LV GLS by −5.4% [95% CI: −9.1% to −1.6%] (P = 0.007). Comparing the change from baseline in LV GLS in the exercise + placebo group (−4.8% [95% CI: −7.4% to −2.2%]; P < 0.0004) to the exercise + IL-6i group (−1.1% [95% CI: −3.8% to 1.6%]; P = 0.42), the exercise + placebo group changed −3.7% [95% CI: −7.4% to −0.02%] (P = 0.049) more than the exercise + IL6i group. However, the interaction effect between exercise and IL-6i was insignificant (4.5% [95% CI: −0.8% to 9.9%]; P = 0.09). Similarly, the exercise + placebo group improved LV global circumferential strain by −3.1% [95% CI: −6.0% to −0.1%] (P = 0.04) more compared to the exercise + IL-6i group, yet we found an insignificant interaction between exercise and IL-6i (4.2% [95% CI: −1.8% to 10.3%]; P = 0.16). There was no effect of IL-6i on exercise-induced changes to volume rates. This study underscores the importance of IL-6 in improving LV GLS in individuals with abdominal obesity suggesting a role for IL-6 in cardiac functional exercise adaptations.