<p>Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to global effects. COVID-19 causes pulmonary and extra-pulmonary manifestations. One of the most common extra-pulmonary manifestations is gastrointestinal (GI) manifestation. Enteric COVID-19 triggers changes in the diversity of gut microbiota (dysbiosis). Dysbiosis of gut flora increases gut permeability, resulting in secondary bacterial infections, systemic inflammation, and injury of the peripheral organs. Dysbiosis may affect the immune system and pulmonary response to the SARS-CoV-2 invasion, suggesting a link between the lungs and gut through the gut-lung axis. Intestinal inflammation caused by SARS-CoV-2 infection induces leaky gut with subsequent transmission of toxins and antigens to the systemic circulation, causing further worsening of the septic condition in COVID-19 patients. Therefore, the anti-inflammatory agents’ interruption of the gut-lung axis may reduce respiratory complications due to intestinal inflammation in COVID-19. Rifaximin (RXM) is a semi-synthetic antibacterial drug derived from natural rifamycin that acts locally within GI by inhibiting bacterial RNA polymerase and reducing the bacterial population and associated intestinal inflammation. RXM inhibits bacterial adherence to the intestinal epithelial lining and translocation across this GI lining. RXM has anti-inflammatory effects by inhibiting the release of pro-inflammatory cytokines and modulating the gut pregnane X receptor (PXR). RXM acts as a prebiotic in maintaining the growth of gut microbiota and may prevent the development of COVID-19-induced dysbiosis. Therefore, RXM could be effective in managing COVID-19 and associated inflammatory complications. Therefore, this review aims to discuss the potential role of RXM in managing COVID-19.</p>