The objective of this study was to achieve an optimal formulation of hydrophilic-hydrophobic conjugates for nano-sized solid dispersions (SDs) with enhanced dissolution of multiple drugs in different gastrointestinal (GI) tract environments. A new conjugate powder with an optimized process was used to fabricate SDs that contained three poorly water-soluble drugs that were also poorly soluble in different dissolution media. The self-assembled nanoparticle formation, drug crystallinity and SD molecular interactions were investigated by measuring the particle size during dissolution testing and physicochemical property analysis (powder X-ray diffraction and Fourier transform infrared spectroscopy). Drug release studies indicated that SD containing conjugated powder significantly improved the dissolution rates of these poorly water-soluble drugs in the GI tract. In addition, particle size analysis showed nano-sized particles in the dissolution media in the early stage with a tendency to reduce smaller particles over time. Physicochemical characterizations demonstrated almost amorphous drug states and hydrogen bonding interactions between the drugs and conjugates in the SD. This study optimized a promising material for SD, and the material was shown to have a promising performance under various pH medium conditions with poorly water-soluble drugs.