Background and Objective: Indigo and indirubin are the main active components of the traditional Chinese medicine Qingdai, known for their heat-clearing, detoxifying, antibacterial, and anti-inflammatory effects. Indirubin has already been applied clinically with proven safety. Both compounds show potential against drug-resistant Helicobacter pylori infection; however, their strong hydrophobicity limits further application. This study aimed to construct food-grade self-assembled nanoparticles using electrostatic and hydrophobic interactions between ovalbumin and fucoidan to efficiently encapsulate indigo and indirubin, thereby improving their solubility and evaluating the in vitro anti- Helicobacter pylori activity and underlying mechanisms of the three formulations. Methods: Nanoparticles were prepared and characterized. The antibacterial activity was assessed using the broth microdilution and checkerboard methods. The mechanisms were further investigated through network pharmacology, molecular docking, electron microscopy, urease activity assay, RT-qPCR, Western blotting, and untargeted metabolomics analyses. Results: At a carrier concentration of 0.75 mg/mL and a drug loading concentration of 40 μg/mL, the nanoparticles exhibited optimal stability, with an encapsulation efficiency of 68.64% and a loading capacity of 3.66%. Indigo, indirubin, and their nanoparticles showed significant inhibitory and bactericidal effects against both sensitive and drug-resistant Helicobacter pylori strains, with minimum inhibitory concentration ranges of 2.5–5, 5–32, and 2.5–5 μg/mL, respectively. The nanoparticles demonstrated superior efficacy and exhibited synergistic or additive effects when combined with antibiotics. The underlying mechanisms involved disruption of bacterial structures; downregulation of virulence genes related to flagella, adhesion, urease, and VacA; inhibition of urease activity and CagA expression; and interference with key metabolic pathways. Conclusion: Encapsulation of indigo and indirubin by the ovalbumin/fucoidan nanoparticle system significantly enhanced their solubility and anti-Helicobacter pylori activity, providing an experimental basis for developing novel natural therapeutics against Helicobacter pylori infection.