This systematic review provides an updated overview of therapeutic strategies against Helicobacter pylori (H. pylori) infection, focusing on the challenges posed by increasing antibacterial resistance and the development of novel treatment options. H. pylori is a gram-negative, spiral-shaped bacterium that infects the stomach and is a major cause of chronic gastritis, peptic ulcers, gastric cancer, and other gastric diseases. Despite the widespread use of standard triple therapy (STT) and quadruple therapy (BQT), the eradication rate of H. pylori has declined due to rising resistance to antibiotics. Emerging therapies, such as the use of new acid blockers like vonoprazan, probiotic adjuvant therapy, and H. pylori vaccines, are being explored as promising alternatives. However, the effectiveness of these treatments requires further evaluation. The prevalence of H. pylori infection varies globally, with higher rates in developing countries and lower rates in developed ones. The infection is highly prevalent in East Asia, with rates as high as 40% in mainland China. In the Americas, the infection rate ranges from 20–30% in Canada and 41.7% in a Mexican community. In Africa, the infection rate is 52.6%, with significant regional variation. The infection is also common in Europe, with an overall rate of 47.5%, and in Oceania, with rates of 24.8% in Australia and 9.2% in New Zealand. H. pylori infection leads to various gastrointestinal and systemic diseases, including chronic gastritis, peptic ulcers, and gastric cancer. It is also associated with cardiovascular diseases, neurological disorders, and other systemic conditions. The morphological form of H. pylori, which can transition between spiral and spherical forms, plays a crucial role in its survival and pathogenicity. The bacterium's ability to form biofilms and utilize efflux pumps contributes to its resistance to antibiotics. The development of new antibacterial treatments for H. pylori infection has been influenced by the increasing resistance to traditional antibiotics. New treatment strategies, such as high-dose dual therapy (HDDT), vonoprazan-containing therapies, and hybrid therapy, have shown higher eradication rates compared to traditional triple or quadruple therapies. However, these treatments may have different side effect profiles and compliance issues. The resistance of H. pylori to antibacterial drugs is a growing concern, with resistance rates to clarithromycin, metronidazole, and levofloxacin increasing globally. In some regions, resistance rates exceed 27%, and in others, they are as high as 39.7%. The development of new vaccines and probiotic interventions is being explored as potential solutions to combat H. pylori infection. Additionally, the use of stimulus-responsive biomaterials, such as pH-sensitive nanoparticles and magnetic field-enhanced nanocThis systematic review provides an updated overview of therapeutic strategies against Helicobacter pylori (H. pylori) infection, focusing on the challenges posed by increasing antibacterial resistance and the development of novel treatment options. H. pylori is a gram-negative, spiral-shaped bacterium that infects the stomach and is a major cause of chronic gastritis, peptic ulcers, gastric cancer, and other gastric diseases. Despite the widespread use of standard triple therapy (STT) and quadruple therapy (BQT), the eradication rate of H. pylori has declined due to rising resistance to antibiotics. Emerging therapies, such as the use of new acid blockers like vonoprazan, probiotic adjuvant therapy, and H. pylori vaccines, are being explored as promising alternatives. However, the effectiveness of these treatments requires further evaluation. The prevalence of H. pylori infection varies globally, with higher rates in developing countries and lower rates in developed ones. The infection is highly prevalent in East Asia, with rates as high as 40% in mainland China. In the Americas, the infection rate ranges from 20–30% in Canada and 41.7% in a Mexican community. In Africa, the infection rate is 52.6%, with significant regional variation. The infection is also common in Europe, with an overall rate of 47.5%, and in Oceania, with rates of 24.8% in Australia and 9.2% in New Zealand. H. pylori infection leads to various gastrointestinal and systemic diseases, including chronic gastritis, peptic ulcers, and gastric cancer. It is also associated with cardiovascular diseases, neurological disorders, and other systemic conditions. The morphological form of H. pylori, which can transition between spiral and spherical forms, plays a crucial role in its survival and pathogenicity. The bacterium's ability to form biofilms and utilize efflux pumps contributes to its resistance to antibiotics. The development of new antibacterial treatments for H. pylori infection has been influenced by the increasing resistance to traditional antibiotics. New treatment strategies, such as high-dose dual therapy (HDDT), vonoprazan-containing therapies, and hybrid therapy, have shown higher eradication rates compared to traditional triple or quadruple therapies. However, these treatments may have different side effect profiles and compliance issues. The resistance of H. pylori to antibacterial drugs is a growing concern, with resistance rates to clarithromycin, metronidazole, and levofloxacin increasing globally. In some regions, resistance rates exceed 27%, and in others, they are as high as 39.7%. The development of new vaccines and probiotic interventions is being explored as potential solutions to combat H. pylori infection. Additionally, the use of stimulus-responsive biomaterials, such as pH-sensitive nanoparticles and magnetic field-enhanced nanoc