Background ‘Helicobacter pylori infection is a widespread global health issue’ associated with chronic gastritis, peptic ulcer disease, and gastric cancer. The increasing resistance to commonly used antibiotics has led to a decline in the effectiveness of standard triple therapy, necessitating the evaluation of alternative treatment regimens. This study compares the efficacy of triple therapy, quadruple therapy, and levofloxacin-based therapy in eradicating H. pylori infection. Methods This comparative observational study was conducted from September 2023 to September 2024 at DHQ Teaching Hospital KDA Kohat, RHQ Hospital Skardu, and Bahria International Hospital Phase 8, Bahria Town Rawalpindi. ‘A total of 120 patients with confirmed H. pylori infection were enrolled and assigned to one of three treatment regimens: standard triple therapy, bismuth-based quadruple therapy, or levofloxacin based therapy’. Treatment adherence, side effects, and eradication success were assessed through follow-up visits. ‘Post-treatment eradication was confirmed using a urea breath test’. Data were analyzed statistically, with significance set at p < 0.05. Results Levofloxacin-based therapy demonstrated the highest eradication rate, followed by quadruple therapy, while triple therapy showed the lowest success rate. The difference in eradication rates among the three regimens was statistically significant (p < 0.05). Patients receiving levofloxacin-based therapy also exhibited better adherence and fewer side effects compared to ‘those in the quadruple therapy group’. ‘The triple therapy group had the highest failure rate’ likely due to antibiotic resistance. Conclusion The findings indicate that levofloxacin-based therapy is the most effective regimen for H. pylori eradication, offering higher success rates and better patient tolerance. Quadruple therapy remains a viable alternative but is associated with more adverse effects. The declining efficacy of triple therapy highlights the need for revised treatment guidelines to address antibiotic resistance. Further research is necessary to monitor resistance patterns and optimize eradication strategies.