This work was aimed to elucidate the mechanism of action of Han-Shi-Yu-Fei-decoction (HSYFD) for treating patients with mild coronavirus disease 2019 (COVID-19) based on clinical symptom-guided network pharmacology. Experimentally, an ultra-high performance liquid chromatography technique coupled with quadrupole time-of-flight mass spectrometry method was used to profile the chemical components and the absorbed prototype constituents in rat serum after its oral administration, and 11 out of 108 compounds were identified. Calculatingly, the disease targets of Han-Shi-Yu-Fei symptoms of COVID-19 were constructed through the TCMIP V2.0 database. The subsequent network pharmacology and molecular docking analysis explored the molecular mechanism of the absorbed prototype constituents in the treatment of COVID-19. A total of 42 HSYFD targets oriented by COVID-19 clinical symptom were obtained, with EGFR, TP53, TNF, JAK2, NR3C1, TH, COMT, and DRD2 as the core targets. Enriched pathway analysis yielded multiple COVID-19-related signaling pathways, such as the PI3K/AKT signaling pathway and JAK-STAT pathway. Molecular docking showed that the key compounds, such as 6-gingerol, 10-gingerol, and scopoletin, had high binding activity to the core targets like COMT, JAK2, and NR3C1. Our work also verified the feasibility of clinical symptom-guided network pharmacology analysis of chemical compounds, and provided a possible agreement between the points of views of traditional Chinese medicine and western medicine on the disease.