Vibrio vulnificus (V. vulnificus) is a useful model for bacterial septicemia as the bacterial infection generates a wide pathogenic spectrum in addition to a high mortality rate. This study was aimed at investigating the effects of genistein on the growth, cytotoxicity, adhesion, and the mouse mortality caused by V. vulnificus. The results of our study indicated that genistein (50 or 100 mg/L) effectively minimized the morphologic damages and inhibited acute death of HeLa cells by V. vulnificus. Strikingly, genistein significantly inhibited the adhesion of V. vulnificus to HeLa cells. This report confirmed that genistein showed bacteriostatic activity against V. vulnificus, but it did not exhibit any bactericidal activity. Nevertheless, genistein (20 mg/kg) effectively decreased CD-1 mice mortality caused by V. vulnificus infection.