Cucumis bisexualis is a favorite wild fruit with high nutritional and medicinal values because of its bioactive constituents. Four previously undescribed coumarin-homoisoflavonoid derivatives (1 – 4), together with seven known coumarin and homoisoflavonoid derivatives (5 – 11) were isolated from the fruits of C. bisexualis for the first time. All the compounds were elucidated by their extensive and comprehensive spectroscopic data and references. Compounds (1 − 11) were evaluated for their hepatoprotective activities in HepG2 cells by the acetaminophen (APAP)-induced damage model at 10.0 μM with bicyclol as the positive control. Among them, compounds 1 , 3 , 5 , and 6 showed moderately hepatoprotective activities to improve the HepG2 cell survival rates from 51.68 ± 2.49% (APAP, 10 mM) to 71.55 ± 4.08%, 65.95 ± 4.39%, 60.77 ± 3.44%, 62.94 ± 2.30%, respectively. Unlabelled Image [ABSTRACT FROM AUTHOR]