Hookworm disease is one of the tropical neglected diseases that significantly impacts human health to varying degrees. Hookworms produce various proteins to facilitate host invasion and immune evasion. Despite available treatments, reinfection is common, underscoring the need for effective vaccines. However, the complexity of the hookworm’s life cycle poses a challenge in understanding the immune response in the vaccine candidates. Reverse vaccinology (RV) offers a powerful approach to understand the immune response by using various bioinformatics tools. This study begins by identifying hookworm antigens capable of inducing host immune responses, followed by docking analysis with different dendritic cell (DC) receptors to investigate the immunological response of antigenic peptides and further correlated to the immunogenicity findings in clinical trial. Necator americanus GlutathioneS-Transferase-1 (Na-GST-1), a known immunogenic protein from Necator americanus, was selected for docking due to its strong antigenic properties. Fifteen DC receptors were evaluated against Na-GST-1, of which seven receptors (TLR2, TLR3, TLR4, TLR7, DEC-205, CD206, and CD36) exhibited stronger predicted interactions, as indicated by stronger binding affinities with Na-GST-1 utilizing various immunoinformatic tools. These receptors are associated with the mediation of Th1/Th2 immune responses, suggesting a potential correlation between docking affinity and the predicted immunogenicity of Na-GST-1. Overall, this study provides valuable insights into DC receptor–antigen interactions and demonstrate a computational approach for assessing the potential of hookworm antigens to engage DC receptors, thereby supporting rational hookworm vaccine design. These findings support the application of early in silico strategies for advancing vaccine candidates against hookworm infection and strengthening control efforts for neglected tropical diseases.