The SARS-CoV-2 pandemic has underscored the urgent need for effective antiviral therapies targeting essential viral enzymes. Among these, the nonstructural protein 12 (nsp12) and nonstructural protein 13 (nsp13), the RNA-dependent RNA polymerase and helicase, respectively, play critical roles in viral RNA synthesis and genome replication. This chapter focuses on the current landscape of small-molecule inhibitors directed against these two targets, having the potential of acting as broad-spectrum antivirals thanks to the high degree of conservation of these viral enzymes. We discuss the structural and mechanistic features of nsp12 and nsp13 that inform inhibitor design, including active-site architecture, nucleotide-binding domains, and cofactor interactions. For nsp12, particular attention is given to nucleoside analogs derived from a drug-repurposing strategy, as well as emerging non-nucleoside inhibitors that target allosteric sites. In the case of nsp13, the development of ATPase and helicase inhibitors remains in early stages, but promising scaffolds have been identified through high-throughput and structure-based screening approaches. For both enzymes, an in-depth discussion of small-molecule inhibitors arisen from both synthetic and natural sources is reported. By integrating biochemical, structural, and medicinal chemistry insights, this chapter provides a comprehensive perspective on targeting SARS-CoV-2 replication through inhibition of nsp12 and nsp13.