Ketogenic diets (KD) are shown to benefit hepatic metabolism; however, their effect on the liver when combined with exercise are unknown. We investigated the effects of a KD vs a 'Western' diet (WD) on markers of hepatic lipid metabolism and oxidative stress in exercising rats. Male and female Wistar rats with access to voluntary running wheels were randomized to three groups (n= 8-14 per group): standard chow (SC; 17% Fat), WD (42% Fat) or KD (90.5% Fat) for 7 weeks. Body fat percentage (BF%) was increased in WD and KD vs SC, although KD females displayed lower BF% vs WD (p≤0.05). Liver triglycerides were higher in KD and WD vs SC, but were attenuated in KD females vs WD (p≤0.05). KD suppressed hepatic markers of de novo lipogenesis (FAS, ACC) and increased markers of mitochondrial biogenesis/content (PGC-1α, TFAM and citrate synthase activity). KD also increased the hepatic GPx1 and lowered oxidized glutathione. Females rats exhibited elevated hepatic markers of mitochondrial biogenesis (TFAM), mitophagy (LC3II/I ratio, ATG 12:5) and cellular energy homeostasis (pAMPK/AMPK) vs males. These data highlight that KD and exercise beneficially impacts hepatic metabolism and oxidative stress and merits further investigation. • Ketogenic diet feeding combined with exercise improved hepatic oxidative stress, suppressed markers of de novo lipogenesis, increased markers of mitochondrial content vs western diet feeding. • Males and females responded similarly to combined ketogenic diet feeding and exercise. • Female rats exhibited elevated hepatic markers of autophagy/mitophagy and energy homeostasis compared with male rats.