Microgravity during long-term space flights induces degeneration of articular cartilage. Artificial gravity through centrifugation combined with exercise has been suggested as a potential countermeasure for musculoskeletal degeneration. The purpose of this study was to investigate the effect of different types of impact loading under normal and artificial gravity conditions on serum concentrations of cartilage oligomeric matrix protein (COMP), a biomarker of cartilage metabolism. Fifteen healthy male adults (26 ± 4 years, 181 ± 4 cm, 77 ± 6 kg) performed four different 30-min impact loading protocols on four experimental days: jumping with artificial gravity elicited by centrifugation in a short-arm centrifuge (AGJ), jumping with artificial gravity generated by low-pressure cylinders in a sledge jump system (SJS), vertical jumping under Earth gravity (EGJ), and running under Earth gravity (RUN). Five blood samples per protocol were taken: 30 min before, immediately before, immediately after, 30 min after, and 60 min after impact loading. Serum COMP concentrations were analyzed in these samples. During the impact exercises, ground reaction forces were recorded. Peak ground reaction forces were significantly different between the three jumping protocols ( < 0.001), increasing from AGJ (14 N/kg) to SJS (22 N/kg) to EGJ (29 N/kg) but were similar in RUN (22 N/kg) compared to SJS. The serum COMP concentration was increased ( < 0.001) immediately after all loading protocols, and then decreased ( < 0.001) at 30 min post-exercise compared to immediately after the exercise. Jumping and running under Earth gravity (EGJ and RUN) resulted in a significantly higher ( < 0.05) increase of serum COMP levels 30 min after impact loading compared to the impact loading under artificial gravity (RUN +30%, EGJ +20%, AGJ +17%, and SJS +13% compared to baseline). In conclusion, both the amplitude and the number of the impacts contribute to inducing higher COMP responses and are therefore likely important factors affecting cartilage metabolism. RUN had the largest effect on serum COMP concentration, presumably due to the high number of impacts, which was 10 times higher than for the jump modalities. Future studies should aim at establishing a dose-response relationship for different types of exercise using comparable amounts of impacts.