The silane coupling agent KH-550 was used to perform surface modification on calcium sulfate whiskers (CSW). Fourier transform infrared spectroscopy and thermogravimetric analysis were used to characterize the effect of surface modification on enhancing the compatibility of CSW with isotactic polypropylene (iPP). Subsequently, the synergetic effect of CSW modified by KH-550 (K-CSW) and aryl amide β-nucleating agent dicyclohexyl-terephthalamide (commercial name: TMB-5) on increasing the relative content of β-crystals and the peak crystallization temperature of iPP was studied. The results showed that KH-550 was a suitable surfactant for surface modification of CSW and K-CSW had certain β-nucleating abilities for iPP. Moreover, for iPP nucleated with the K-CSW/TMB-5, the higher peak crystallization temperature and relative content of β-crystals (Kβ = 0.84) were achieved, which were obviously better than those of iPP nucleated with K-CSW or TMB-5 independently, demonstrating that K-CSW/TMB-5 was a novel highly efficient compound β-nucleating agent for iPP and had certain synergistic effect for formation of β crystals.