Next-generation sequencing (NGS) has reformed infectious disease management, including COVID-19. While real-time polymerase chain reaction (PCR) is widely used for rapid pathogen detection, it requires predefined targets. NGS offers an unbiased approach, detecting multiple pathogens simultaneously without prior knowledge. Despite its potential, NGS implementation in clinical settings faces challenges like high costs and technical complexity. NGS platforms like Illumina, Ion Torrent, and Nanopore provide high-throughput sequencing, identifying pathogens and resistance markers. Applications include whole genome sequencing (WGS), metagenomic NGS (mNGS), and targeted NGS (tNGS). Integrating NGS with conventional methods could improve diagnostics, but current evidence is mixed for supporting its widespread clinical use.