Despite the widespread use of Covid-19 vaccines, there is still a global need to find effective therapeutics to deal with the variants of SARS-CoV-2. Moslae Herba (MH) is a herbal medicine crediting with antiviral effect. The study aims to investigate the antiviral effects and the underlying mechanism of aqueous extract from MH (AEMH) for treating SARS-CoV-2. The in vitro anti-SARS-CoV-2 activity of AEMH was evaluated using cell viability and viral load. Component analysis was performed by HPLC-ESI-Q-TOF/MS. The connection between Covid-19 and AEMH was constructed by integrating network pharmacology and transcriptome profile to seek the core targets. The components with antiviral activities were analyze by molecular docking and in vitro pharmacological verification. AEMH exerted anti-SARS-CoV-2 effects through inhibiting viral replication and reducing cell death caused by infection (IC50 is 170 μg/mL for omicron strain). A total of 26 components were identified from AEMH. Through matching 119 intersection targets of ‘disease and drug’ with 1082 differentially expressed genes Covid-19 patients, nine genes were screened. Of the nine, PNP and TPI1 genes were identified as core targets as AEMH treatment significantly regulated the mRNA expression level of the two genes on infected cells. Three components, caffeic acid, luteolin, and rosmarinic acid displayed antiviral activities in verification. Molecular docking also demonstrated they could form stable bonds with the core targets. This study explored the antiviral activity and possible mechanism of AEMH for treating SARS-CoV-2, which could provide basic data and reference for clinical application of MH.