Chitosan/alginate nanoparticles (DG1-NPs and DG1/Cur-NPs) aiming to enhance the oral antithrombotic activity of clam heparinoid DG1 were prepared by ionotropic pre-gelation. The influence of parameters, such as the concentration of sodium alginate (SA), chitosan (CTS), CaCl2, clam heparinoid DG1, and curcumin (Cur), on the characteristics of the nanoparticles, were investigated. Results indicate that chitosan and alginate can be used as polymer matrices to encapsulate DG1, and nanoparticle characteristics depend on the preparation parameters. Nano-particles should be prepared using 0.6 mg/mL SA, 0.33 mg/mL CaCl2, 0.6 mg/mL CTS, 7.2 mg/mL DG1, and 0.24 mg/mL Cur under vigorous stirring to produce DG1-NPS and DG1/Cur-NPS with small size, high encapsulation efficiency, high loading capacity, and negative zeta potential from approximately −20 to 30 mV. Data from scanning electron microscopy, Fourier-transform infrared spectrometry, and differential scanning calorimetry analyses showed no chemical reaction between DG1, Cur, and the polymers; only physical mixing. Moreover, the drug was loaded in the amorphous phase within the nanoparticle matrix. In the acute pulmonary embolism murine model, DG1-NPs enhanced the oral antithrombotic activity of DG1, but DG1/Cur-NPs did not exhibit higher antithrombotic activity than DG1-NPs. Therefore, the chitosan/alginate nanoparticles enhanced the oral antithrombotic activity of DG1, but curcumin did not further enhance this effect.