Patients with major infectious diseases are at high risk of secondary hospital-acquired infections due to compromised immune function and the high burden of environmental contamination with hospital-acquired infection pathogens in the admitting departments. These infections are predominantly endogenous or environmentally acquired exogenous infections, are difficult to recognize early, and represent a weak point in hospital-acquired infection prevention and control. Building upon standard hospital-acquired infection prevention and control strategies, this prevention and control pathway proposes systematic enhanced measures targeting the above-mentioned specific risks. This pathway includes protecting patients' own microbiota, safeguarding open body cavities, active screening and decolonization, built environment control, and environmental cleaning and disinfection. It also recommends a closed-loop management system through infection surveillance and review, post-discharge follow-up, and environmental sampling. This pathway aims to provide healthcare facilities with a reference framework for targeted prevention and control to reduce the incidence of secondary hospital-acquired infections in patients with major infectious diseases and to ensure patient safety.