Scope Perinatal maternal obesity and excessive fructose consumption have been associated with liver metabolic diseases. The study investigates whether moderate maternal high‐fat diet affects the liver mitochondria responses to fructose intake in adult offspring. Methods and Results Wistar female rats have received a standard diet (mSTD) or high‐fat diet (mHFD) (9% and 28.6% fat, respectively), before mating until the end of lactation. Male offspring were fed standard diet from weaning to adulthood and received water or fructose‐drinking water (15%) from 120 to 150 days old. Fructose induces liver mitochondrial ultrastructural alterations with higher intensity in mHFD offspring, accompanied by reduced autophagy markers. Isolated mitochondria respirometry shows unaltered ATP‐coupled oxygen consumption with increased Atp5f1b mRNA only in mHFD offspring. Fructose increases basal respiration and encoding complex I‐III mRNA, only in mSTD offspring. Uncoupled respiration is lower in mHFD mitochondria that are unable to exhibit fructose‐induced increase Ucp2 mRNA. Fructose decreases antioxidative defense markers, increases unfolded protein response and insulin resistance only in mHFD offspring without fructose‐induced hepatic lipid accumulation. Conclusion Mitochondrial dysfunction and homeostatic disturbances in response to fructose are early events evidencing the higher risk of fructose damage in the liver of adult offspring from dams fed an isocaloric moderate high‐fat diet. Perinatal maternal ingestion of an isocaloric and moderate high‐fat diet (mHFD) promotes hepatic mitochondrial and metabolic alterations in adult male offspring. The offspring maladaptation causes unique responses to fructose chronic ingestion, such as insulin resistance, unfolded protein response (UPR) pathway activation, and intensification of the fructose‐induced mitochondria damage accompanied by inability to increase the respiratory chain mitochondrial genes expression.