Abstract The physiological processes underlying hemodynamic homeostasis can be modulated by muscle activity and gravitational loading. The effects of leg muscle activity on cardiovascular regulation have been observed during orthostatic stress. Here, we evaluated such effects during head-down tilt (HDT). In this posture, the gravitational gradient along the body is different than in upright position, leading to increased central blood volume and reduced venous pooling. We compared the cardiovascular signals obtained with and without leg muscle loading during HDT in healthy human subjects, both at rest and during recovery from leg-press exercises using a robotic device. Further, we compared such cardiovascular responses to those obtained during upright position. Loading leg muscles during HDT at rest led to significantly higher values of arterial blood pressure than without muscle loading, and restored systolic values to those observed during upright posture. Maintaining muscle loading post-exercise altered the short-term cardiovascular responses, but not the values of the signals five minutes after the exercise. These results suggest that leg muscle activity modulates cardiovascular regulation during HDT. This modulation should therefore be considered when interpreting cardiovascular responses to conditions that affect both gravity loading and muscle activity, for example bed rest or microgravity.