Licorice(Glycyrrhizae Radix or Liquiritiae Radix) is traditionally used to treat various diseases including inflammation and gastric ulcers. Licorice is rich in flavonoid compounds and possesses anti-inflammatory activities. To investigate the protective effects of licorice flavonoids(LFs) in both acetic acid-induced and dextran sulphate sodium(DSS)-induced ulcerative colitis(UC) mouse model and its underlying mechanism. Acute UC was induced by intra-rectal acetic acid(4% v/v) after pretreatment with LFs(100, 200, and 400 mg/kg, p.o.), 0.9% saline(20 mL/kg, p.o.) or Sulfasalazine(SASP)(600 mg/kg, p.o.) for 10 d. Quantitative analysis of chemical components of LFs was also conducted by HPLC. Our results showed that pre-treatment with LFs significantly reduced the wet weight/length ratio of colon, percentage of affected area, macroscopic and histological damage scores in acid-induced UC mice. LFs also significantly decreased the oxidative stress and pro-inflammatory cytokines, upregulated nuclear factor erythroid 2-related factor 2(Nrf2) pathway and downregulated nuclear transcription factor kappa B(NF-κB) pathway. At last, LFs also showed obvious antiulcer effect on the DSS-induced UC model. The major components of LFs were licochalcone A, glabrone, licoflavone, and licoflavone B. This study demonstrates that the protective effect of LFs may at least in part be due to its anti-oxidant activity through Nrf2 pathway and anti-inflammatory activity through NF-κB pathway. Licorice (Glycyrrhizae Radix or Liquiritiae Radix) is traditionally used to treat various diseases including inflammation and gastric ulcers. Licorice is rich in flavonoid compounds and possesses anti-inflammatory activities. To investigate the protective effects of licorice flavonoids (LFs) in both acetic acid- induced and dextran sulphate sodium (DSS) -induced ulcerative colitis (UC) mouse model and its underlying mechanism. Acute UC was induced by intra-rectal acetic acid (4% v / v) after pretreatment with LFs (100, 200, and 400 0.9% saline (20 mL / kg, po) or Sulfasalazine (SASP) (600 mg / kg, po) for 10 d. Quantitative analysis of chemical components of LFs was also conducted by HPLC. Our results showed that pre-treatment with LFs significantly reduced the wet weight / length ratio of colon, percentage of affected area, macroscopic and histological damage scores in acid-induced UC mice. LFs also significantly decreased the oxidative stress and pro- inflammatory cytokines, upregulate At last, LFs also showed significant antiulcer effect on the DSS-induced UC model. The major components of LFs were licochalcone A, glabrone, licoflavone, and licoflavone B. This study demonstrates that the protective effect of LFs may at least in part be due to its anti-oxidant activity through Nrf2 pathway and anti-inflammatory activity through NF-κB pathway.