<p>The microgravity, radiation, and high-stress environment of space present unique challenges to astronauts’ physical and mental health. In this environment, interactions between the host and pathogens are altered, thereby increasing astronauts’ risk of endogenous viral infections. Notably, viral shedding detected during spaceflight does not necessarily indicate clinically significant disease, and the distinction between molecular reactivation, productive viral replication, and symptomatic infection must be carefully considered. This review aims to ensure mission success and enhance space biocapacity and biodefence by summarizing case studies and reactivation mechanisms of endogenous latent herpesviruses, the latest prevention and control strategies, and the challenges posed by host variability and antiviral efficacy in the space environment.</p>