Treatment of aggressive triple-negative breast cancer (TNBC) is still challenging. Isoliquiritigenin (ISL) is a water-insoluble bioactive compound possessing high anti-TNBC capacity with less toxicity. The present study aimed to develop a safe and effective oral drug delivery system to improve the oral efficacy of ISL for TNBC therapeutics. ISL-loaded zein phosphatidylcholine hybrid nanoparticles (ISL@ZLH NPs) were constructed by a one-step solvent evaporation method. Optimization and characterization of ISL@ZLH NPs were performed. Cellular uptake in vitro and biodistribution of ZLH NPs in vivo were investigated. The pharmacokinetics of ISL@ZLH NPs in terms of ISL content in the plasma, organs, and tumor tissues were validated, and the anti-TNBC efficacy was evaluated. Encapsulation efficiency (96.75 ± 1.41%) and drug loading efficiency (6.56 ± 0.83%) were found in ISL@ZLH NPs. ISL@ZLH NPs were able to enhance the absorption of ISL in the tumor sites. Moreover, the upregulation of p27 and downregulation of EGFR and CDK4 were observed in ISL@ZLH NPs treated tumors. Collectively, oral intake of ISL@ZLH NPs would be translated into a potential clinical therapy strategy against TNBC.