This review article aims to significantly advance the scientific community's efforts to develop effective nucleoside‐based drugs for treating severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and other emerging infectious diseases. This study concentrates on the main viral protease (Mpro) and explores nucleoside‐based compounds as potential therapeutic agents. This investigation investigated the impact of acylation‐induced modifications on the nucleoside hydroxyl group and subsequent properties. Nucleoside analogs, which are recognized for their diverse biochemical properties, were synthesized and rigorously screened to evaluate their antimicrobial efficacy. In the domain of pharmaceutical research, computational pharmacokinetics has emerged as a critical tool, especially in the pursuit of nucleoside analogs as potential therapeutics. In silico methods aid in predicting pharmacokinetic traits, interactions with crucial enzymes, and the stability of these analogs in biological environments, thereby streamlining drug design and reducing experimental costs. Concurrently, computational studies revealed the intricate interactions between the analogs and the active site of the main protease. The amalgamation of experimental screening and computational insights underscores the emergence of potent nucleoside candidates with inhibitory activity against SARS‐CoV‐2 Mpro. Additionally, this review integrates computational studies that provide valuable insights into the interactions between nucleoside analogs and the main protease of SARS‐CoV‐2.