Helicobacter pylori and humans have one of the most complex relationships in nature. How a bacterium manages to live in one of the harshest and hostile environments is a topic of unraveling mysteries. H. pylori is a prevalent species and it colonizes the human gut of more than 50% of the world population. It infects the epithelial region of antrum and persists there for a long period. Over the time of evolution, H. pylori has developed complex strategies to extend the degree of inflammation in gastric mucosa. H. pylori needs specific adaptations for initial colonization into the host environment like helical shape, flagellar movement, chemotaxis, and the production of urease enzyme that neutralizes acidic environment of the stomach. There are several factors from the bacterium as well as from the host that participate in these complex interactions. On the other hand, to establish the persistent infection, H. pylori escapes the immune system by mimicking the host antigens. This pathogen has the ability to dodge the immune system and then persist there in the form of host cell, which leads to immune tolerance. H. pylori has an ability to manipulate its own pathogen‐associated molecular patterns, which leads to an inhibition in the binding with specific pattern recognition receptors of the host to avoid immune cell detection. Also, it manipulates the host metabolic homeostasis in the gastric epithelium. Besides, it has several genes, which may get involved in the acquisition of nutrition from the host to survive longer in the host. Due to the persistence of H. pylori, it causes chronic inflammation and raises the chances of gastric cancer. This review highlights the important elements, which are certainly responsible for the persistence of H. pylori in the human host.