Introduction: Gastrointestinal (GI) cancers are considered among the most important causes of mortality and morbidity. Helicobacter pylori infection has been proven to be highly associated with the development of a variety of gastric diseases such as chronic gastritis, peptic ulcer disease (PUD), mucosa-associated lymphoid tissue (MALT), and gastric cancer (GC). To date, the exact role of the virulence factors in gastric diseases and other diseases remains elusive and controversial. Methods: The present study is a classic systematic review (expert opinion), in which articles published in English and Persian languages derived from Web of Science, Scopus, PubMed, and Iranian databases, including Magiran, IranMede, and scientific information database (SID) without any time limitation were explored using standardized keywords of H. pylori, virulence factors, gastric cancer, a combination of the above words, and other synonymous keywords. Finally, the information and obtained results were collected and interpreted. Results: In total, 14 of the 172 articles reviewed had inclusion criteria with the approval of the responsible author. According to the results, the development of chronic bacterial inflammation due to pathogenic mechanisms and factors, especially the role of cagA and vacA genes in gastric cancer, remains an important medical problem. Conclusions: Each of the H. pylori virulence factors can have a role in cancer development, and it appears that on-time H. pylori treatment is one of the best methods to prevent gastric cancer. Therefore, targeting Pathogenic factors of H. pylori to induce apoptosis and stimulate the immune system will be a promising, attractive, and helpful method for cancer prevention.