Helicobacter pylori (H. pylori) is a widespread bacterium affecting over half the global population, leading to chronic gastritis, peptic ulcers, and gastric cancer. As a significant public health concern, it underscores the need for effective primary care strategies, especially amid rising antibiotic resistance and the absence of a vaccine. Addressing the challenge of H. pylori eradication remains critical, particularly given the prevalence of antibiotic resistance. In this context, a comparative study evaluated the efficacy of moxifloxacin-based triple therapy versus levofloxacin-based sequential therapy as first-line treatments for H. pylori infection. The research, involving 162 patients, aimed to assess treatment outcomes and identify factors influencing eradication success rates. Results demonstrated a significantly higher eradication rate (81.2% ITT, 92% PP) with moxifloxacin-based therapy compared to levofloxacin-based treatment. Moreover, patients in the moxifloxacin group experienced fewer side effects (p-value <0.005), indicating its favorable safety profile. Notably, higher patient compliance (p-value 0.111) was observed in the moxifloxacin group, suggesting better tolerability and adherence. Demographic and clinical factors played a crucial role in treatment outcomes. In the moxifloxacin group, females exhibited higher eradication rates(COR: 6.417, p-value: 0.019), while individuals without dyspepsia (COR: 0.101, p-value: 0.001) showed decreased rates. Conversely, in the levofloxacin group, patients with comorbidities (COR: 1.731, p-value: 0.406) and absence of dyspepsia (COR: 0.251, p = 0.005) or premature fullness(COR: 2.79, p = 0.034) exhibited better outcomes. Dyspepsia and premature fullness emerged as significant predictors of eradication success in the levofloxacin group. Overall, the presence of gastric/duodenal ulcers, absence of dyspepsia, and abdominal pain significantly influenced eradication rates across both treatment groups. The study underscores the efficacy of moxifloxacin-based triple therapy as a superior first-line treatment for H. pylori infection, particularly in Pakistan. Moving forward, tailored approaches considering demographic and clinical variables are essential to optimize eradication efforts. Further research is warranted to refine treatment strategies and enhance eradication success rates, ultimately advancing cancer prevention in populations at risk of H. pylori-associated malignancies.