We aimed to assess the effects of muscle disuse on muscle strength (MS), muscle mass (MM) and cardiovascular fitness. Databases were scrutinized to identify human studies assessing the effects of muscle disuse on both (1) MM and (2) maximal oxygen uptake (VO2max) and/or MS. Random-effects meta-analysis and meta-regression with initial physical fitness and length of the protocol as a priori determined moderators were performed. We quantitatively analyzed 51 different studies, and the level of significance was set at p<0.05. Data from the participants in 14 studies showed a decline in both VO2max (SMD: -0.93; 95% CI: -1.27 to -0.58) and MM (SMD: -0.34; 95% CI: -0.57 to -0.10). Data from 47 studies showed a decline in strength (-0.88; 95% CI: -1.04 to -0.73) and mass (SMD: -0.47; 95% CI: -0.58 to -0.36). MS loss was twice as high as MM loss, but differences existed between anatomical regions. Notably, meta-regression analysis revealed that initial MS was inversely associated with MS decline. VO2max and MS decline to a higher extent than MM during muscle disuse. We reported a more profound strength loss in subjects with high muscular strength. This is physiologically relevant for athletes because their required muscular strength can profoundly decline during a period of muscle disuse. It should however be noted that a period of muscle disuse can have devastating consequences in old subjects with low muscular strength.