The replication machinery of SARS-CoV-2 is a primary target for therapeutic intervention, and has led to significant progress in antiviral medication discovery. This review consolidates contemporary molecular insights into viral replication and rigorously assesses treatment methods at different phases of viruses’ clinical development. Direct-acting antivirals, such as nucleoside analogs (e.g., remdesivir, molnupiravir) and protease inhibitors (e.g., nirmatrelvir), have shown clinical effectiveness in diminishing morbidity and hospitalization rates. Simultaneously, host-targeted medicines like baricitinib, camostat, and brequinar leverage critical host–virus interactions, providing additional pathways to reduce viral replication while possibly minimizing the development of resistance. Notwithstanding these advancements, constraints in distribution methods, antiviral longevity, and the risk of mutational evasion demand novel strategies. Promising investigational approaches encompass CRISPR-mediated RNA degradation systems, inhalable siRNA-nanoparticle conjugates, and molecular glue degraders that target host and viral proteins. Furthermore, next-generation treatments aimed at underutilized enzyme domains (e.g., NiRAN, ExoN) and host chaperone systems (e.g., TRiC complex) signify a transformative approach in antiviral targeting. The integration of high-throughput phenotypic screening, AI-driven medication repurposing, and systems virology is transforming the antiviral discovery field. An ongoing interdisciplinary endeavor is necessary to convert these findings into versatile, resistance-resistant antiviral strategies that are applicable beyond the present pandemic and in future coronavirus epidemics.

SARS-CoV-2 replication remains a critical and main target for therapeutic interventions. The current review synthesizes existing knowledge to provide an in-depth analysis of molecular insights and both current and emerging therapy methods, moving past reviews centered on antivirals and general replication processes. We examined antiviral tactics aimed at these replication pathways, including direct-acting nucleoside analogs (remdesivir, molnupiravir), protease inhibitors (nirmatrelvir), and host-directed agents influencing viral entry and RNA synthesis. Emphasizing therapeutic constraints and evolutionary escape, this study also investigates synergistic drug combinations and resistance mechanisms. Discussed for their capacity to efficiently handle next coronavirus dangers are emerging methods—from CRISPR-based gene-silencing, nanoparticle-delivered siRNAs, and AI-driven drug discovery. Highlighted as new antiviral targets are host-pathogen interactions including adaptation via the TRiC complex and phosphatase pathways. This paper offers a road map for improving therapeutic tactics against SARS-CoV-2 and related developing viruses with molecular virology, pharmacology, and computational biology.