Amiodarone (AM) is a drug commonly used in patients with ventricular arrhythmias. It can damage vascular endothelial cells and easily cause phlebitis. At present, the prevention and treatment of phlebitis induced by the use of AM is not clear due to the lack of corresponding primary research. Isoliquiritigenin (ISL) has an anti-inflammatory effect, but until now, has not been explored much in the field of research in primary care nursing. The purpose of this study is to investigate the efficacy and mechanism of action of ISL in treating phlebitis induced by AM. In our study, we used human umbilical vein endothelial cells (HUVECs) that were divided into three groups: the NC group (normal), the AM group (AM 30 μmol/L for 24 h), and the ISL pretreatment group (isoliquiritigenin 10 μmol/L after 1 h of pretreatment with amiodarone for 24 h). We used CCK-8 to detect cell proliferation, cell scratch assay to detect the migration capability of cells, flow cytometry to measure apoptosis, angiogenesis assay to check the total length and total branches of angiogenesis, and PCR and WB to detect the expression of PCNA, casepase-3, and VEGFA. WB was used to detect NF-κBp65 and p-NF-κBp65 expression. Compared with the AM group, the ISL pretreatment promoted cell proliferation and migration, inhibited cell apoptosis, increased the total length and total branches of angiogenesis, and downregulated p-NF-κBp65 expression. ISL shows promise in the prevention and treatment of clinical phlebitis and can be used as a potential therapeutic drug to prevent phlebitis.