Oxetanocin A (Oxt-A), a novel oxetanosyl N-glycoside nucleoside, was isolated from Bacillus megaterium in 1986. It carries an oxetane ring on the sugar moiety of the nucleoside scaffold, which contributes to differences in its structure from those of common tetrahydrofuranyl-based nucleosides. In view of the unique 3D-spatial framework, the complete synthesis of Oxt-A has been achieved by multiple research groups. The pharmacological properties of this natural product have also been broadly investigated by pharmacists and chemists since its discovery. Notably, the potential antiviral effect of Oxt-A has captured attention of researchers in the field of antiviral agent development. Furthermore, epidemic outbreaks caused by viruses have been stimulating the preparation and modification of various Oxt-A analogs over the past few decades. However, none of the studies have overviewed the antiviral efficacies of this naturally occurring scaffold yet. Thus, the present review summarizes the synthesis, structural modification, and antiviral activities of Oxt-A and its derivatives. We believe that these comprehensive descriptions will provide a novel perspective for the discovery of antivirus drugs with well-improved performance and pave newer paths for combating sudden public health issues triggered by viruses in the future.