Moderate endurance exercise leads to an improvement in cardiovascular performance, stress resilience, and blood function. However, the influence of chronic endurance exercise over several hours or days is still largely unclear. We examined the influence of a non-stop 160.9/230 km ultramarathon on body composition, stress/cardiac response, and nutrition parameters. Blood samples were drawn before (pre) and after the race (post) and analyzed for ghrelin, insulin, irisin, glucagon, cortisol, kynurenine, neopterin, and total antioxidant capacity. Additional measurements included heart function by echocardiography, nutrition questionnaires, and body impedance analyses. Of the 28 included ultra-runners (7f/21m), 16 participants dropped out during the race. The remaining 12 finishers (2f/10m) showed depletion of antioxidative capacities and increased inflammation/stress (neopterin/cortisol), while energy metabolism (insulin/glucagon/ghrelin) remained unchanged despite a high negative energy balance. Free fat mass, protein, and mineral content decreased and echocardiography revealed a lower stroke volume, left end diastolic volume, and ejection fraction post race. Optimizing nutrition (high-density protein-rich diet) during the race may attenuate the observed catabolic and inflammatory effects induced by ultramarathon running. As a rapidly growing discipline, new strategies for health prevention and extensive monitoring are needed to optimize the athletes’ performance.