As a weak base, the solubility of nilotinib (NH) decreases with increasing pH resulting in low bioavailability via oral administration. In our study, NH was selected as a model drug to explore a supersaturating drug delivery system (SDDS) to improve the absorption and bioavailability of BCS IV drugs. Certain excipients were used to prevent or delay the precipitation of NH after pH increment. Hence, the solid dispersions of NH were synthesized in the presence of either Eudragit E100 (ESD) or Soluplus (SSD), respectively. Both ESD and SSD are proven to rapidly dissolve in the acidic dissolution medium, forming supersaturated NH solutions after the pH increment to 6.8, while the supersaturated solution of NH was kept stable for a sufficient time period. NH was found to exist in the microcrystalline form in the ESD and amorphous form in the SSD. The relative bioavailability of ESD and SSD in rats was 222% and 219%, respectively, compared with NH suspension, suggesting that the two formulations developed in our study significantly improved the oral absorption of NH. Overall, SDDS represents a promising strategy to improve the oral bioavailability of NH and such platform technology may be explored to other BCS II or IV drugs with poor solubility.