Consumption of high-fructose diets early in life increases the risk of developing metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). Zingerone, an alkaloid isolated from Zingiber officinale, has been demonstrated to reverse obesity and fatty liver in adult male rats. We investigated the potential preventive effects of neonatally administered zingerone on the development of fructose-induced NAFLD in male and female rats. Four-day-old male (n = 35) and female (n = 44) rat pups were randomized and gavaged with: 10 mL/kg body weight (bwt) of distilled water (C), 10 mL/kg bwt of 20% fructose solution (Fr), 10 mL/kg bwt of 20% fructose solution +40 mg/kg bwt of zingerone (ZFr), and 40 mg/kg bwt of zingerone (Z) daily for 14 days. After weaning, all groups continued on unlimited standard rat feed; however, groups C and Z had plain drinking water, whereas groups Fr and ZFr had unlimited 20% fructose solution to drink for 10 weeks. Rats on the high-fructose diet (Fr) compared with the negative controls (C) had significantly increased hepatic lipid content (in %, males: P = .0002; females: P < .0001, analysis of variance [ANOVA]) and hepatic steatosis score (in %, males: P = .0018; females: P < .0022, Kruskal-Wallis ANOVA). Zingerone prevented (P < .05) the fructose-induced increase in hepatic steatosis in both sexes. The plasma alanine aminotransferase activity, levels of uric acid, TBARS (thiobarbituric acid reactive substances), IL-6 (interleukin-6), and TNF-α (tumor necrosis factor alpha) were not different (P > .05, ANOVA) across the different treatment groups in both sexes. No difference (P > .05, ANOVA) was observed between the two sexes for treatment, sex and interaction effects with regard to hepatic lipid content, and measured blood parameters. The use of zingerone neonatally should be further investigated as a strategic prophylactic intervention for the prevention of long-term high-fructose diet-induced NAFLD. © Copyright 2021, Mary Ann Liebert, Inc., publishers, and Korean Society of Food Science and Nutrition 2021.