In water-rich mines, water conservancy, and hydropower projects, the rock mass is immersed in water for a long time, which leads to changes in its mechanical properties and affects the safety and stability of the engineering rock mass. Based on the long-term immersion of rock mass with intermittent joints by water, uniaxial compression tests were carried out on prefabricated intermittent jointed sandstone with five inclinations (0°, 30°, 45°, 60°, 90°) and three connectivity ratios (0.25, 0.50, 0.75) under different immersion times to study sandstone with intermittent joints’ mechanical response and deterioration mechanism. The research shows that: (1) With the increase of the joint inclination, the compressive strength and elastic modulus of the sandstone with intermittent joints first decreased and then increased, showing a U-shaped distribution. The compressive strength and elasticity of the sample with an inclination of 60° reach the minimum value; at the initial stage of immersion, the deterioration effect of the sample is more significant, and the deterioration effect decreases gradually with the increase in immersion time; in the initial stage of water immersion, the deterioration effect of the sample is more significant, and with the increase of the immersion time, the deterioration effect gradually weakens. (2) Immersion time and joint inclination have a great influence on the included angle, number, and mode of failure cracks. With the increase in immersion time, the plastic characteristics of the sample increase obviously, showing the characteristics of loose and weak; with the increase in joint inclination, the failure mode of the sample gradually changes from tension failure to tension shear failure, and tension failure. The influence degree of joints on failure is weak-induction-control-induction. (3) Under the water–rock action, the cement between mineral particles of the sample is gradually dissolved, the cementation of mineral particles is weakened, and the mineral particles develop into layered and flake structure, which gradually evolves from dense structure to porous loose structure. (4) The deterioration mechanism of the mechanical properties of the sandstone with intermittent joints under the water–rock action was analyzed from the perspectives of physics, chemistry, and mechanics. The deterioration of the mechanical properties of the sample is a process of gradual accumulation of damage.