An acute bout of endurance exercise in adults stimulates a same‐day anti‐inflammatory response which may affect low‐grade chronic inflammation and insulin resistance and benefit cardio‐metabolic health. The anti‐inflammatory responses to intermittent games‐based exercise and to exercise in young people beyond 2 hours post‐exercise are unknown. Thus, the purpose of the present study is to examine the anti‐inflammatory, glycemic and insulinemic response to games‐based activity in adolescents. Following ethical approval and familiarization, 39 adolescents (12.3 ± 0.7 years) completed an exercise (E) and rested (R) trial in a counterbalanced, randomized crossover design. Following a standardized breakfast, participants completed 1‐hour games‐based activity. Capillary blood samples were taken at baseline, immediately and 1 hour post‐exercise, and 30, 60 and 120 minutes following a standardized lunch. A final blood sample was taken the next morning. Data were analyzed using repeated measures ANOVA. IL‐6 concentration was higher on day one of the exercise trial (E:3.4 ± 0.4, R:2.7 ± 0.4 pg/mL; P = 0.006), as was the anti‐inflammatory IL‐6:TNF‐α ratio (E:5.53 ± 0.93, R:3.75 ± 0.45; P = 0.027). Levels of the anti‐inflammatory cytokine IL‐10 increased on day two of the exercise trial (E:2.11 ± 0.23, R:1.66 ± 0.16 pg/mL; P = 0.032). Insulin sensitivity was enhanced on the exercise trial with a reduction in iAUC following the standardized lunch (E:2310 ± 834, R:3122 ± 1443 mU/L × 120 minutes; P < 0.001). Games‐based activity stimulated an anti‐inflammatory response up to 24 hours post‐exercise and improved insulin sensitivity in response to a standardized meal in healthy adolescents. These novel findings suggest that games‐based activity is an ecologically valid mode of exercise to elicit beneficial effects on cardio‐metabolic risk factors in young people.