Alterations in cerebral hemodynamics in microgravity are hypothesized to occur during spaceflight and could be linked to the Visual Impairment and Intracranial Pressure syndrome. Head-down tilt (HDT) is frequently used as a ground-based analog to simulate cephalad fluid shifts in microgravity; however, its effects on cerebral hemodynamics have not been well studied with MRI techniques. Here, we evaluate the effects of 1) various HDT angles on cerebral arterial and venous hemodynamics; and 2) exposure to 1% CO2 during an intermediate HDT angle (−12°) as an additional space-related environmental factor. Blood flow, cross-sectional area (CSA), and blood flow velocity were measured with phase-contrast MRI in the internal jugular veins, as well as the vertebral and internal carotid arteries. Nine healthy male subjects were measured at baseline (supine, 0°) and after 4.5 h of HDT at −6°, −12° (with and without 1% CO2), and −18°. We found a decrease in total arterial blood flow from baseline during all angles of HDT. On the venous side, CSA increased with HDT, and outflow decreased during −12° HDT ( P = 0.039). Moreover, the addition of 1% CO2 to −12° HDT caused an increase in total arterial blood flow ( P = 0.016) and jugular venous outflow ( P < 0.001) compared with −12° HDT with ambient atmosphere. Overall, the results indicate decreased cerebral blood flow during HDT, which may have implications for microgravity-induced cerebral hemodynamic changes.