This study is to prepare a nanosuspension based on poly(lactic-co-glycolic acid) (PLGA) for delivery, controlled release and enhanced anti-solid tumor effects of As2O3. As2O3-loaded PLGA nanocapsules (As2O3-PLGA NCs) were prepared by double emulsion-solvent evaporation method and were optimized by univariate analysis in combination with orthogonal experimental according to several factors. The optimized As2O3-PLGA NCs presented suitable physical stability, favorable size of (200.2±10.6) nm (PDI=0.117±0.008), spherical shape, and high encapsulation efficiency (92.48%±2.14%). The in vitro suspension stability of the NCs was excellent. The release of As2O3 from the NCs showed pH responsive release characteristics. The NCs can be efficiently taken up by SMMC-7721 cell and showed excellent antitumor efficacy against SMMC-7721 cell line. Then, As2O3-PLGA NCs could be considered as a promising formulation for the pH dependent release of As2O3 in cancer cells and enhance the anti-solid tumor effects of As2O3.