Irritable bowel syndrome (IBS) with diarrhea predominance is a subtype of IBS characterized by recurrent abdominal pain or discomfort along with frequent loose or watery stools. A significant number of individuals are impacted and are physically, socially, and emotionally impacted. Managing diarrhea predominant IBS (IBS D) involves a multidimensional approach due to unpredictable nature of the condition involving lifestyle modifications, dietary changes, stress management techniques, and medications. Altered gut microbiota and small intestinal bacterial overgrowth (SIBO) often precede IBS leading to dysbiosis. Systemic antibiotics and other treatment options have been reported with varied outcomes, yielding inconsistent results. Rifaximin, with its broad anti bacterial action, along with eubiotic activity, limited systemic exposure, gut specific action, and limited potential for drug interactions along with metronidazole is proposed as a novel treatment option for IBS D. Rifaximin and metronidazole fixed dose combination will not only address infectious diarrhea associated with IBS but also SIBO and postinfectious IBS with excellent efficacy and tolerability. For patients with IBS D, rifaximin along with metronidazole can be a new treatment avenue as increasing evidence supports the hypothesis that bacterial overgrowth may be involved in the pathogenesis of IBS and parasitic infections can be a triggering factor for the exacerbation of IBS. PubMed and Google Scholar were searched through May 2023. Randomized controlled trials and reviews published in English were selected that evaluated rifaximin and/or metronidazole in patients with IBS.