The incidence of microbial resistance is growing, and new rescue regimens are needed to treat Helicobacter pylori (H. pylori) infection. This study aimed to evaluate levofloxacin-based quadruple therapies’ efficacy, safety, and tolerability in eradicating H. pylori. In a randomized, double-blind clinical trial, 220 patients with dyspepsia and H. pylori infection were randomly assigned to receive either bismuth subcitrate 240 mg, pantoprazole 20 mg, amoxicillin 1000 mg twice a day, and levofloxacin 500 mg daily for seven days (BPAL-7) or ten days (BPAL-10). The eradication of H. pylori was evaluated two months after the end of treatment, and adverse drug reactions (ADRs) were assessed during the intervention. According to intention-to-treat and per-protocol, the eradication rate was significantly lower in the BPAL-7 regimen at 49.1% (95% CI: 39.3–57.8) and 47.6% (95% CI: 39.7–58.4), respectively, compared to the BPAL-10 regimen at 62.7% (95% CI: 53.6–72.8) and 62.4% (95% CI: 55.1–72.8), respectively. The ADR incidence was not statistically significant between the groups of BPAL-7 (33.6%) and BPAL-10 (36.7%). Although the ADRs were negligible in both groups, these regimens could not be an ideal alternative therapy for H. pylori because of their low eradication rates compared to standard regimens. Trial Registration. The study was reviewed and approved by the Iranian Registry of Clinical Trials (IRCT201406141155N19).