Fenretinide (4-HPR), a retinoid derivative, has shown high antitumor activity, a low toxicological profile, and no induction of resistance. Despite these favorable features, the variability in oral absorption due to its low solubility combined with the high hepatic first pass effect strongly reduce clinical outcomes. To overcome the solubility and dissolution challenges of poorly water-soluble 4-HPR, we prepared a solid dispersion of the drug (4-HPR-P5) using a hydrophilic copolymer (P5) previously synthesized by our team as the solubilizing agent. The molecularly dispersed drug was obtained by antisolvent co-precipitation, an easy and up-scalable technique. A higher drug apparent solubility (1134-fold increase) and a markedly faster dissolution were obtained. In water, the colloidal dispersion showed a mean hydrodynamic diameter of 249 nm and positive zeta potential (+41.3 mV), confirming the suitability of the formulation for intravenous administration. The solid nanoparticles were also characterized by a high drug payload (37%), as was also evidenced by a chemometric-assisted Fourier transform infrared spectroscopy (FTIR) investigation. The 4-HPR-P5 exhibited antiproliferative activity, with IC50 values of 1.25 and 1.93 µM on IMR-32 and SH-SY5Y neuroblastoma cells, respectively. Our data confirmed that the 4-HPR-P5 formulation developed herein was able to increase drug apparent aqueous solubility and provide an extended release over time, thus suggesting that it represents an efficient approach to improve 4-HPR bioavailability.