Here, solid dispersion (SD) techniques were utilized to improve the oral bioavailability of tadalafil (TDF). Poly(vinyl pyrrolidone-covinyl acetate) (PVP/VA S-630; 60% VP and 40% VA; MW 50,000) SD formulations were previously found to improve the solubility and dissolution (%) of TDF. The effect of various weak acids and bases on SD formulations was also investigated herein. PVP/VA S-630 SD formulations in combination with weak acids and bases increased the apparent solubility of TDF. After 1 h, the apparent solubility of PVP/VA S-630 SD formulations with MgO, meglumine, and tartaric acid were significantly higher by 387.0 ± 4.17, 376.8 ± 9.88, and 308.8 ± 4.17 μg/mL, respectively, than those of SD formulations without weak acids and bases (166.8 ± 0.50 μg/mL). The dissolution (%) of SD formulations with weak acids was under 60%; however, the dissolution (%) of those containing MgO, meglumine, and NaHCO3 was over 80% in distilled water (specifically 85.6%, 89.9%, and 91.6%, respectively). The optimal SD formulation contained meglumine (B-2); both its apparent solubility after 24 h and dissolution (%) were the highest among all SD formulations. The B-2 SD formulation showed no toxicity in Caco-2 cells after 24 h. The area under the concentration-time curve (AUClast) and peak plasma concentration (Cmax) of the orally administered B-2 SD formulation was greater than that with Cialis® powder in rats. We conclude that the B-2 SD formulation significantly improves the apparent solubility and dissolution (%) of TDF over that of commercially available products (i.e., Cialis®). Moreover, the B-2 SD formulation improves the relative bioavailability (BA) of TDF (21.9%) over that of Cialis®.