This study investigated the effect of natural aquatic medium and human digestive media on the dissolution of single and mixture of nanoparticles. We determined an in-vitro dissolution factor for a mixture of nanoparticles in human digestive media. The oral exposure scenario was considered in this study, with exposure of nanoparticles through surface water containing a mixture of nanoparticles. The dissolution of these nanoparticles was tracked through the human gastrointestinal tract, including saliva, gastric, and intestinal artificial fluids. The dissolution factors for ZnO and CuO nanoparticles were found to be 68% and 54% in mixture suspension at 10 mg/L nanoparticle concentration, respectively. A comparison between single and mixture of nanoparticles showed a significant difference in ion contents in various mediums, thus indicating the effect of the simultaneous presence of two nanoparticles on extents of dissolution. The presence of antibiotics in the aquatic system along with mixture of nanoparticles decreased CuO nanoparticle dissolution factor to 21% and for ZnO, dissolution factor was found to be 77%. Both particulate fraction and ionic fraction for single and mixture of nanoparticles were reported in this study. Digestive loading values associated with NPs was found to be 6.2 and 5.4 mg/L for ZnO and CuO nanoparticles, respectively. Such data is essential in assessing exposure dose and characterizing human health risk. This data also helps in understanding risk associated with nanoparticles and ionic part separately for the mixture system.