Helicobacter pylori (H. pylori) is one of the most common pathogenic agents of human which infects approximately 50% of the world’s population. The colonization of this gram-negative bacterium in gastric mucosa often has an implication on several gastrointestinal (GI) diseases including gastro-duodenal ulcer and gastric cancer. The eradication of infection is the most effective strategy to decrease the infection rate and prevalence of gastro-duodenal complications. However, development of antibiotic-resistant strain throughout the world hindered the therapeutic efficacies against the bacterium. Extensive studies on the molecular mechanisms underlying antibiotic resistance indicated that upon infection, H. pylori enter and occupy the gastric epithelium and encase themselves in an extracellular polymeric substance known as biofilm. The biofilm structure protects the bacterial colony from any external threat and contributes to several chronic and recurrent infection of GI tract. Furthermore, bacterial aggregates in biofilm are 1000 times more resistant to any type of antibiotics as compared to solitary bacteria. Thus, currently anti-biofilm agents are being explored as a novel therapeutic alternative of antibiotics to combat the drug-resistance strategies of H. pylori infection. This review focuses on the molecular mechanisms of biofilm formation of H. pylori in gastric mucosa and the associated drug resistance strategy of biofilm producing H. pylori. Additionally, efforts are made to compile the existing knowledge of the antibiofilm agents which are designed for the treatment of H. pylori induced gastric infection.