In view of the high infection rate of Helicobacter pylori, a safe and effective vaccine is urgently needed. Recent trends in vaccine design have shifted toward safe and specific epitope‐based vaccines. In this study, by using different immunoinformatics approaches, a total of eight linear B cell epitopes, four HTL and three CTL epitopes of FlaA and UreB proteins of H. pylori G27 strain were screened out, we also predicted the conformational epitopes of the two proteins. Then, the dominant epitopes were sequentially linked by appropriate linkers, and the cytotoxic T lymphocyte–associated antigen 4 extracellular domain was attached to the N‐terminal of the epitope sequence. Meanwhile, molecular docking, molecular dynamics simulations and principal component analysis were performed to show that the multi‐epitope vaccine structure had strong interactions with B7 (B7‐1, B7‐2) and Toll‐like receptors (TLR‐2, ‐4). Eventually, the effectiveness of the vaccine was validated using in silico cloning. These analyses suggested that the designed vaccine could target antigen‐presenting cells and had high potency against H. pylori, which could provide a reference for the future development of efficient H. pylori vaccines.