Although the major therapeutic uses of the proton pump inhibitors are in gastric-acid related diseases, evidences are suggestive of a pleiotropic nature of the compounds . We comment on the probable pathways and cellular machineries via which proton pump inhibitors could show beneficial therapeutic effects against SARS-CoV-2 based on the existing evidences . Proton pump inhibitors have shown antiviral potencies in various in vivo and in vitro studies . Some of the major possible ways through which they can act against SARS-CoV-2 are by exerting anti-inflammatory and anti-fibrotic effects, via vacuolar ATPase pumps leading to raised endolysosomal pH and by targeting endosomal complexes . The current pandemic has put forward a challenge to find treatment options . Although the potential roles of proton pump inhibitors against SARS-CoV-2 have been discussed in recent publications, the clinical evidences for their real-world effectiveness do not point towards a beneficial effect clearly yet . We suggest that although proton pump inhibitors should strongly be considered as potential therapeutic options for COVID-19, larger studies in the form of randomized controlled trials would be required to arrive at a definite conclusion.