Helicobacter pylori is a bacterium associated with gastric diseases and disorders of the upper gastrointestinal tract. The gram-negative bacterium Helicobacter pylori is known as a persistent colonizer of the human stomach, and this bacteria is also involved in extra-intestinal diseases. In 1994, the International Agency for Research on Cancer, World Health Organization classified H. pylori as a class 1 carcinogen, the only bacterium given this classification. Besides, the emergence of H. pylori resistance to antibiotics has been a major clinical challenge in the field of gastroenterology, and this concern has been shown an increasing tendency in many regions of the world. To overcome the current circulating difficulties, new potential therapeutic targets were uncovered to find active substances for the treatment of H. pylori infection. Several medicinal plants and their isolated compounds have been reported for their antimicrobial activity against H. pylori. It is demonstrated that they are efficacious against H. pylori strains that are resistant to drugs. The mechanism of action of many of these plant extracts and plant-derived compounds is different from that of conventional antibiotics. Therefore, natural compounds are emerging as a potential source of raw materials with diverse mechanisms of action. Some commonly known mechanisms can be listed as anti-urease activity, anti-adhesive activity, anti-inflammatory and gastroprotective activity, and effects on the oxidative stress process. Recently, new classes of drugs with reasonable antibacterial mechanisms against H. pylori have also been mentioned, including (1) anti-biofilm agents, (2) anti-virulence molecules (anti-VacA, anti-CagA agents, toxin BabA and LPS inhibitors, anti-motility agents, Helicobacter pylori quorum sensing inhibitors), (3) mucolytic agents, and (4) compounds that impact on essential proteins in the physiology of H. pylori such as inosin-5‘monophosphate dehydrogenase and HsrA inhibitors. This review article aims to summarize current prospects, identify possible novel targets, and be considered as a complementary therapy in the eradication treatment against Helicobacter pylori.