It has been demonstrated that individuals exposed to actual or simulated microgravity often experience cardiovascular dysfunctions when returning to Earth. The underlying mechanisms of orthostatic intolerance and countermeasure treatment are still poorly understood. In this paper, the progress in the mechanism of cardiovascular deconditioning from the view of vascular remodeling, increased venous compliance in the lower limbs, cellular proliferation and differentiation, and cell signaling pathway was reviewed. Meanwhile, an overview of the countermeasures including exercise, lower body negative pressure, thigh cuffs, traditional Chinese herb medicine and artificial gravity was presented.