Increased susceptibility of circadian clock mutant mice to metabolic diseases has led to the idea that a molecular clock is necessary for metabolic homeostasis. However, these mice often lack a normal feeding-fasting cycle. We tested whether time-restricted feeding (TRF) could prevent obesity and metabolic syndrome in whole-body Cry1;Cry2 and in liver-specific Bmal1 and Rev-erbα/β knockout mice. When provided access to food ad libitum, these mice rapidly gained weight and showed genotype-specific metabolic defects. However, when fed the same diet under TRF (food access restricted to 10 hr during the dark phase) they were protected from excessive weight gain and metabolic diseases. Transcriptome and metabolome analyses showed that TRF reduced the accumulation of hepatic lipids and enhanced cellular defenses against metabolic stress. These results suggest that the circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding and fasting and by maintaining balance between nutrient and cellular stress responses. Display omitted •TRF protects clock mutant mice from obesity without changes in activity or calories•TRF restores rhythms in feeding-fasting, metabolic, and nutrient-sensing pathways•TRF prevents fatty liver, dyslipidemia, and glucose intolerance in clock mutant mice•TRF transcriptional program activates cellular homeostasis maintenance pathways Chaix et al. show that time-restricted feeding (TRF; 10 hr access to food during the active phase) can improve metabolic health in mice with a compromised circadian clock. Their results point to metabolic dysfunction as secondary to disrupted behavioral rhythms (e.g., feeding-fasting), and which can be redressed by TRF.