Antimicrobial resistance (AMR) constitutes a global public health crisis that undermines clinical infection control and human health outcomes. JUC, a FDA- and CE-certified physical antimicrobial spray dressing, is a novel alternative to chemical antimicrobials, utilizing water-soluble organosilicon quaternary ammonium salt (Si-QAS) to form a dual-layer nano-film on biological tissues and medical device surfaces. This nano-film exerts broad-spectrum antimicrobial effects via a physical electrostatic mechanism, eliminating the risk of drug-resistant strain development while providing long-acting infection prevention. This systematic review synthesizes peer-reviewed preclinical, clinical, and mechanistic research on JUC, including its molecular structure, dual-layer nano-film formation mechanism, physical antimicrobial action, preclinical efficacy, clinical outcomes across diverse indications, safety profile, regulatory status, and comparative advantages over conventional antimicrobial strategies. It also identifies critical research gaps and future directions for the translation and optimization of JUC in global infection control. A comprehensive literature search was conducted across PubMed, Embase, Web of Science, and Chinese biomedical databases (CNKI, WanFang) for studies published up to 2026, with strict inclusion criteria for original research, clinical trials, and mechanistic investigations. The review confirms JUC’s efficacy in reducing hospital-acquired infections (HAIs) and treating microbial skin/wound infections, with a favorable safety profile and unique advantages in addressing AMR.