The aim of this study was to investigate hydrophilic-hydrophobic conjugates as new carriers for nano-sized solid dispersions (SDs). The amphiphilic conjugates were prepared via an esterification reaction between hydroxypropyl methylcellulose (HPMC) and zein. Four formulations of conjugates were investigated with different ratios of zein to HPMC (1:5, 1:10, 1:20, and 1:40). Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy and particle size analyses were performed to characterize and optimize the formulation for SD. Isradipine and prednisolone were chosen as poorly water-soluble drugs for SD using the conjugate as a carrier. Dissolution tests, particle size analyses, powder X-ray diffraction and FTIR were conducted to determine the dissolution enhancement and its mechanism. The conjugate formed small particles as a self-assembled carrier. Although the SD with isradipine or prednisolone showed a small increase in particle size, the dissolution rate of those drugs in SD increased significantly compared to pure drugs. The interaction between the drug and conjugate was attributed to the formation of small particles and changes to the drug crystallinity. This study demonstrated that the hydrophilic-hydrophobic conjugate is a promising material for SD, with the potential of reducing drug particles to nano size in addition to promoting drug amorphousness or molecular interactions.