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As a traditional Chinese medicine, Shuang-Huang-Lian (SHL) has been widely used for treating infectious diseases of the respiratory tract such as encephalitis, pneumonia and asthma. During the past few decades, considerable research has focused on the pharmacological action, pharmacokinetic interaction with antibiotics and clinical applications of SHL. A huge and more recent body of pharmacokinetic study supports the combination of SHL and antibiotics has different effects such as antagonism and synergism. SHL has been one of the best-selling traditional Chinese medicine (TCM) products. However, there is no system review of SHL preparations, ranging from protection against respiratory tract infections to interaction with antibiotics. Since their important significance in clinical therapy, the pharmacodynamic, pharmacokinetic, and interactions with antibiotics of SHL were reviewed and discussed. In addition, this review attempts to explore the possible potential mechanism of SHL preparations in prevention and treatment of COVID-19. We are concerned about what is known of the effects of SHL against virus, bacterium, and its interactions with antibiotics, providing a new strategy for expanding the clinical research and medication of SHL preparations.