Background: Vonoprazan-based regimens are anticipated to have higher Helicobacter pylori eradication rates than PPIs. Aim and objective: to compare between the effectiveness of two 14-day regimens; one based on vonoprazan and the other on esomeprazole, to eradicate H. pylori. Patients and methods: Participants were determined to have active H. pylori infection and were either untreated or had previously received therapy were randomly assigned to either the VAL group (vonoprazan 20 mg bid, amoxicillin 1000 mg bid, plus levofloxacin 500 mg once day) or the EAL group (Esomeprazole 20 mg bid., amoxicillin 1000 mg bid., and levofloxacin 500 mg once daily). After 4-6 weeks following the end of the therapy, an H. pylori antigen test was used to determine the degree of eradication. Results: A number of 122 individuals were randomly assigned to either the VAL (n = 61) or EAL (n = 61) groups, and 118 patients were successful in completing the study. The eradication rates of H. pylori were found to be 97.7 percent for the VAL group and 68.5 percent for the EAL group, respectively (P = 0.031). All adverse treatment-related occurrences were minor and did not differ substantially between the two groups, such as nausea and vertigo. Conclusions: The VAL regimen was well tolerated and led to increased eradication rates; as a result, VAL may be thought of as a powerful regimen for treating H. pylori, particularly in nations with high levels of antibiotic resistance.