Human spaceflight has been fascinating man for centuries, representing the intangible need to explore the unknown, challenge new frontiers, advance technology, and push scientific boundaries further. A key area of importance is cardiovascular deconditioning, that is, the collection of hemodynamic changes—from blood volume shift and reduction to altered cardiac function—induced by sustained presence in microgravity. A thorough grasp of the 0G adjustment point per se is important from a physiological viewpoint and fundamental for astronauts’ safety and physical capability on long spaceflights. However, hemodynamic details of cardiovascular deconditioning are incomplete, inconsistent, and poorly measured to date; thus a computational approach can be quite valuable. We present a validated 1D–0D multiscale model to study the cardiovascular response to long-term 0G spaceflight in comparison to the 1G supine reference condition. Cardiac work, oxygen consumption, and contractility indexes, as well as central mean and pulse pressures were reduced, augmenting the cardiac deconditioning scenario. Exercise tolerance of a spaceflight traveler was found to be comparable to an untrained person with a sedentary lifestyle. At the capillary–venous level significant waveform alterations were observed which can modify the regular perfusion and average nutrient supply at the cellular level. The present study suggests special attention should be paid to future long spaceflights which demand prompt physical capacity at the time of restoration of partial gravity (e.g., Moon/Mars landing). Since spaceflight deconditioning has features similar to accelerated aging understanding deconditioning mechanisms in microgravity are also relevant to the understanding of aging physiology on the Earth.