Helicobacter pylori, one of the top carcinogens, is associated with most cases of gastric cancer-related deaths worldwide.Over the past two decades, the rising rates of antibiotic resistance in the bacterium have reduced the efficacy of conventional antibiotic-based treatments.This underscores the urgency for continued research and novel treatment approaches. Establishing a worldwide accepted physician guideline for antibiotic prescription is crucial to combat antibiotic resistance and improveH. pyloriinfection management. Therefore, it is important to address the challenges thatcomplicatethe establishment of a universally accepted treatment protocol to prescribe an antibiotic regimen to eradicateH. pylori. The answers to the questions of why conventional standard triple therapy remains a first-line treatment choice despite its low efficacy, and how different factors affect therapy choice, are needed to identify these challenges. Hence, this review addresses concerns related toH. pyloritreatment choice, role of antibiotic resistance and patient compliance in treatment outcomes, first-line vs. second-line therapy options, and methods for enhancing existing treatment methods. We also present a chart to aid antibiotic treatment prescription, which may support physician guidelines in this aspect. Eradication ofH. pyloriand patient adherence is paramount in overcoming antibiotic resistance in the bacterium, and our chart summarizes key considerations and suggests novel approaches to achieve this goal.