Niclosamide is a promising antitumor agent, but its low aqueous solubility places limit on its antitumor efficacy. The aim of this study was to improve the solubility and dissolution of niclosamide through using octenylsuccinate hydroxypropyl phytoglycogen (OHPP), an amphiphilic dendrimer-like biopolymer. The niclosamide-OHPP solid dispersion (niclo-OHPP SD) was prepared and characterized in terms of crystallinity, molecular interactions, solubility and dissolution profile, in-vitro antitumor efficacy, and in-vitro transdermal amount. X-ray powder diffraction analysis showed the amorphous state of niclosamide in niclo-OHPP SD. FTIR showed the formation of hydrogen bonding between niclosamide and OHPP. Solubility of niclosamide with niclo-OHPP SD was about 11,914 times that of niclosamide alone, and 61% of niclosamide with niclo-OHPP SD dissolved in 3 h upon dissolution. Against three cancer cell lines, cytotoxicity assays indicated greater inhibition by using niclo-OHPP SD than by using DMSO-assisted niclosamide solution. The cumulative transdermal amount of niclosamide with niclo-OHPP SD was 5.3 times that with niclosamide alone. This study showed that the use of OHPP could provide strong support for the development of niclosamide-based drug formulations.