Introduction and objectives: Patients with disorders of the gut-brain axis, such as irritable bowel syndrome (IBS), often exhibit small intestinal bacterial overgrowth (SIBO). Its treatment includes rifaximin (RF), ciprofloxacin (CF), neomycin, sulfamethoxazole-trimethoprim, and metronidazole (MZ). RF is a non-absorbable antibiotic, postulated to have fewer adverse effects. Our aim was to assess symptomatic response and SIBO eradication in patients with IBS, using three antibiotic regimens. Methods: A prospective, randomized, double-blind study was conducted on IBS patients over 18 years of age, utilizing the Rome IV questionnaire and lactulose breath test. Those diagnosed with SIBO were randomly assigned to receive antibiotic treatment. Group A was treated with RF, group B with CF, and group C with MZ, each for 10 days. Treatment response was evaluated based on the SIBO eradication rate 15 days after completing therapy, utilizing hydrogen and methane breath tests with lactulose. Self-reported symptoms were recorded on a 10-point Likert scale before, during, and after treatment. Results: Ninety-seven patients with IBS and SIBO were included, 81% of whom completed treatment. Fifty-nine percent of the patients treated with RF achieved SIBO eradication, compared with 53% and 79% of those treated with CR and MZ, respectively. Metronidazole reduced more methane levels, compared with the other groups. However, the greatest reduction in abdominal pain and bloating was observed in the RF group, with a lower percentage of adverse events. Conclusions: Patients with IBS and SIBO benefit from antibiotic therapy. MZ exhibited the best SIBO eradication rate, but RF demonstrated greater symptomatic improvement and a lower rate of adverse effects.