Background Astronauts in space consume fewer calories and return to earth predisposed to orthostatic intolerance. The role that caloric deficit plays in the modulation of autonomic control of the cardiovascular system is unknown. Therefore, the purpose of this study was to determine the effects of 6° head-down bedrest (an analog of spaceflight) with a hypocaloric diet (25 % caloric restriction) (CR) on autonomic neural control during static handgrip (HG) and cold pressor (CP) tests. Nine healthy young men participated in a randomized crossover bedrest (BR) study, consisting of four, two-week interventions (hypocaloric ambulatory, hypocaloric bedrest, normocaloric ambulatory, and normocaloric bedrest), each separated by 5 months. Heart rate (HR), arterial pressure, and muscle sympathetic nerve activity (MSNA) were recorded before, during, and after HG (40 % of maximum voluntary contraction to fatigue), post-exercise muscle ischemia (forearm occlusion), and CP. Bedrest and nutritional combinations were compared using two-way ANOVA with repeated measures. Results HR, MSNA, and the change in systolic blood pressure during HG were attenuated with caloric restriction, but post-intervention responses for all groups were similar during post-exercise muscle ischemia. CR was associated with a higher diastolic blood pressure during CP; however, HR was directionally opposite (i.e., increase with BR, decrease with CR). Conclusions In summary 14-day caloric/fat restriction attenuated MSNA and pressor responses during isometric exercise to fatigue but not to post-exercise muscle ischemia. This indicates that the integrity of the metaboreflex is maintained whereas the influence of the mechanoreflex and/or central command may be reduced.