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A liposome of Licochalcone A (LCA‐Liposomes) was purposively prepared to ameliorate the low in vivo availability and efficacy of LCA. Physical characterization of LCA‐Liposomes was carried out mainly by determining particle size, morphology, zeta potential (Z‐potential), and efficiency of LCA encapsulation (EE) via appropriate techniques. Also, the rate of LCA release in vitro and distribution in vivo (plasma and tissues) was evaluated. Evaluation of the antirenal activity of LCA‐liposomes was carried out by establishing chronic renal failure (CRF) model in mice through intragastric administration of adenine (200 mg/kg) and subsequent determination of biochemical parameters and examination of tissue sections. Respectively, the mean size of liposomal particles, Z‐potential and EE of LCA‐Liposomes were 71.78 ± 0.99 nm, −38.49 ± 0.06 mV, and 97.67 ± 1.72%. Pharmacokinetic and tissue distribution studies showed that LCA‐Liposomes could improve the availability of LCA in the blood and tissues, whereas during pharmacodynamics studies, the liposome effectively improved the therapeutic effect of LCA on CRF mice by potentially protecting the renal tissues while exhibiting antioxidant activity. In conclusion, LCA‐Liposomes could effectively improve the bioavailability of LCA and provide platform for the development of LCA‐related functional products. Practical applications: As a traditional Chinese medicine, licorice is widely used in food and pharmaceutical industries. LCA is a small molecule flavonoid extracted from the root of licorice. In this study, LCA was loaded on liposome carriers, which significantly improved the water solubility and oral bioavailability, and proved that LCA‐Liposomes have certain therapeutic effects on chronic renal failure, thereby providing a basis for the development of LCA into drugs or functional food in the future. [ABSTRACT FROM AUTHOR]