Helicobacter pylori remains a major cause of gastritis. Rising antibiotic resistance worldwide has undermined traditional therapies, leading to the decline of standard clarithromycin-based triple therapy, necessitating new treatment strategies. In this review, we summarize advances in H. pylori pharmacotherapy, including the use of novel agents (e.g., the potassium-competitive acid blocker vonoprazan and rifabutin-containing regimens), optimized regimens (such as 10–14 day bismuth quadruple therapy), and adjunctive approaches (probiotics). We highlight region-specific challenges, such as developing countries with high H. pylori prevalence and limited resources, where eradication rates with standard therapies can be extremely low. We also discuss how personalized approaches, including antibiotic susceptibility testing, local resistance surveillance, and even artificial intelligence (AI)-driven decision tools, can guide regimen choice (triple vs. quadruple vs. salvage) to maximize success. Cost considerations are also addressed, noting that expensive treatments, may limit their use especially in low-resource settings. Finally, we outline future directions, such as integrating AI into clinical support systems and expanding access to diagnostics, to improve H. pylori management, patient adherence, maximize treatment efficacy, minimize antimicrobial misuse, and improve global eradication success rates.