Purpose Long-term physical activity is reported to improve chronic systemic inflammation, which provides protection against the ensuing development of chronic disease. Accordingly, the present study assessed changes in pro- and anti-inflammatory cytokines, aerobic capacity and body composition following 8 weeks of either small-sided games (SSG) or cycling (CYC) training compared to a sedentary control (CON) condition. Methods Thirty-three middle-aged, sedentary men were randomized into CYC (n = 11), SSG (n = 11), or CON (n = 11) conditions. The CYC and SSG conditions trained 3 days/week for 8 weeks, whilst CON maintained habitual activity and dietary patterns. Pre- and post-intervention testing included a dual-energy X-ray absorptiometry scan, sub-maximal (80 % maximal heart rate) aerobic capacity (VO2) and fasting venous blood. Venous blood measures for pro-inflammatory markers included C-reactive protein (CRP), interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and leptin; anti-inflammatory markers included IL-10, IL-1 receptor agonist, and adiponectin. Results Both CYC and SSG increased submaximal power output and VO2 (P < 0.05), decreased total body fat-mass (TB-FM; P < 0.05), and CRP (SSG, −0.45 ± 0.42 mg L−1; P = 0.008; CYC, −0.44 ± 0.59 mg L−1; P = 0.02). Only SSG increased total body fat-free mass (TB-FFM; +1.1 ± 1.2 kg; P = 0.001) and decreased concentration of plasma IL-6 (−0.69 ± 0.62 pg mL−1; P = 0.002) and leptin (−2,212 ± 2,531 ng mL−1; P = 0.014). Conclusion Cycling and SSG training were both effective at improving CRP, VO2 and TB-FM. Furthermore, SSG training has also shown to be an effective training approach in reducing IL-6 and leptin and increasing muscle mass within sedentary, middle-aged men.