The severe acute respiratory syndrome coronavirus 2, also known as SARS-CoV-2, is the causative agent of the COVID-19 global pandemic. SARS-CoV-2 has a highly conserved non-structural protein 12 (NSP-12) involved in RNA-dependent RNA polymerase (RdRp) activity. For the identification of potential inhibitors for NSP-12, computational approaches such as the identification of homologous proteins that have been previously targeted by FDA-approved antivirals can be employed. Herein, homologous proteins of NSP-12 were retrieved from Protein DataBank (PDB) and the evolutionary conserved sequence and structure similarity of the active site of the RdRp domain of NSP-12 was characterized. The identified homologous structures of NSP-12 belonged to four viral families: Coronaviridae, Flaviviridae, Picornaviridae, and Caliciviridae, and shared evolutionary conserved relationships. The multiple sequences and structural alignment of homologous structures showed highly conserved amino acid residues that were located at the active site of the RdRp domain of NSP-12. The conserved active site of the RdRp domain of NSP-12 was evaluated for binding affinity with the FDA-approved antivirals, i.e., Sofosbuvir and Dasabuvir in a molecular docking study. The molecular docking of Sofosbuvir and Dasabuvir with the active site that contains conserved motifs (motif A-G) of the RdRp domain of NSP-12 revealed significant binding affinity. Furthermore, MD simulation also inferred the potency of Sofosbuvir and Dasabuvir. In conclusion, targeting the active site of the RdRp domain of NSP-12 with Dasabuvir and Sofosbuvir might reduce viral replication and pathogenicity and could be further studied for the treatment of SARS-CoV-2.