Exercise-induced muscle damage (EIMD) is characterized by a reduction in functional performance, disruption of muscle structure, production of reactive oxygen species, and inflammatory reactions. Ginseng, along with its major bioactive component ginsenosides, has been widely employed in traditional Chinese medicine. The protective potential of American ginseng (AG) for eccentric EIMD remains unclear. Twelve physically active males (age: 22.4 ± 1.7 years; height: 175.1 ± 5.7 cm; weight: 70.8 ± 8.0 kg; peak oxygen consumption [$\dot{\mathrm{V}}{\mathrm{O}}_2$peak] 54.1 ± 4.3 mL/kg/min) were administrated by AG extract (1.6 g/day) or placebo (P) for 28 days and subsequently challenged by downhill (DH) running (−10% gradient and 60% $\dot{\mathrm{V}}{\mathrm{O}}_2$peak). The levels of circulating 8-iso-prostaglandin F 2α (PGF2α), creatine kinase (CK), interleukin (IL)-1β, IL-4, IL-10, and TNF-α, and the graphic pain rating scale (GPRS) were measured before and after supplementation and DH running. The results showed that the increases in plasma CK activity induced by DH running were eliminated by AG supplementation at 48 and 72 h after DH running. The level of plasma 8-iso-PGF2α was attenuated by AG supplementation immediately (p = 0.01 and r = 0.53), 2 h (p = 0.01 and r = 0.53) and 24 h (p = 0.028 and r = 0.45) after DH running compared with that by P supplementation. Moreover, our results showed an attenuation in the plasma IL-4 levels between AG and P supplementation before (p = 0.011 and r = 0.52) and 72 h (p = 0.028 and r = 0.45) following DH running. Our findings suggest that short-term supplementation with AG alleviates eccentric EIMD by decreasing lipid peroxidation and promoting inflammatory adaptation.