Acute-on-chronic liver failure (ACLF) is a severe syndrome of liver diseases commonly seen in clinical practice and can lead to severe disorders and decompensation of liver synthesis, metabolism, detoxification, and biotransformation, as well as multiple organ failure and an extremely high short-term mortality rate. Infection can induce or aggravate the condition of ACLF and is an independent influencing factor for patient prognosis. This article describes the mechanism and characteristics of ACLF with infection, summarizes the common types and clinical features of infection, reviews the recommended anti-infective regimens, and emphasizes the importance of early prophylactic treatment. ACLF patients with infection tend to have critical conditions, and early diagnosis and empirical anti-infective treatment is the key to successful treatment.