The widespread adoption of high-intensity interval training raises a critical question: does the specific exercise type matter for immune system adaptation? This distinction could reshape how fitness enthusiasts and health practitioners approach HIIT protocols for optimal inflammatory benefits. A crossover study with 26 healthy young adults compared treadmill running versus stationary cycling HIIT sessions, measuring inflammatory markers at multiple time points. Both modalities elevated interleukin-6 immediately post-exercise and increased the anti-inflammatory cytokine IL-10 after 24 hours. However, treadmill running produced a more pronounced inflammatory cascade, with IL-8 concentrations rising immediately and continuing to climb throughout the 24-hour recovery period—a pattern absent in cycling. C-reactive protein also showed substantial elevation trends only after treadmill sessions. This differential immune response likely stems from the greater mechanical stress and eccentric muscle contractions inherent in running versus the smoother, concentric-focused cycling motion. The findings suggest that weight-bearing HIIT may provide superior inflammatory training stimulus, potentially leading to stronger adaptive responses over time. For longevity-focused individuals, this research indicates that incorporating running-based intervals could optimize the hormetic stress response that drives cellular resilience. However, the higher inflammatory burden also implies greater recovery demands, making cycling HIIT potentially preferable for frequent training or older adults seeking HIIT benefits with reduced inflammatory stress.