The objective of this paper is to investigate the coupling effect of cement and organosilicon hydrophobic agents on the water resistance of phosphogypsum. Different weight ratios of Portland cement were added to adjust the alkalinity of this system and further improve the work efficiency of the organosilicon hydrophobic agents. Some macroscopic performances, such as the water absorption, the compressive strength, the flexural strength, and the softening coefficient, were measured to characterize the water-resistance of phosphogypsum. The microscopic characteristics were analyzed via contact angle tests, scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) to understand the mechanism of organosilicon hydrophobicity. The results indicated that both the compressive and flexural strengths of phosphogypsum first increased and then decreased with the increase of organosilicon hydrophobic agents. Meanwhile, the surface contact angle continued to increase and the softening coefficient exhibited an obvious increase. When the hydrophobic agent was combined with Portland cement, the softening coefficient of phosphogypsum further increased from 0.80 to 0.99, while the water absorption rate was significantly reduced from 16.0% to 0.8%. Microscopic tests proved that the hydrophobic organic molecules can be polymerized under the high alkalinity, and promote the formation of a hydrophobic film, thus significantly improving the water-resistance of phosphogypsum.