The circadian clock is an important molecular oscillator that temporally orchestrates mammalian physiology to optimize nutrient metabolism and storage. Increasing evidence has implicated a disrupted circadian clock as a major driver of metabolic diseases such as nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms by which a dysfunctional circadian clock causes NAFLD are poorly understood. Our transcriptome studies in human patients with NAFLD and progressing liver fibrosis show an important role for the circadian core clock regulator BMAL1. To delineate the mechanisms by which BMAL1 drives NAFLD and fibrosis, we challenged Bmal1 knockout mice with either high fat diet or leptin deficiency. Surprisingly, while these mice developed obesity and had impaired lipid metabolism and storage, they were protected against insulin resistance, inflammation, hepatic steatosis and fibrosis. Further studies revealed that this protection against liver disease was caused by alterations in growth and sex hormone pathways. Specifically, male mice showed a feminized liver and white adipose tissue transcriptome that correlated with lower growth hormone and testosterone levels and elevated estradiol concentrations. These endocrine adaptations were also consistent with the transcriptional profiles observed in human NAFLD or during liver fibrosis progression, providing novel opportunities for clinical translation. Collectively, we provide the first evidence that endocrine adaptations induced by BMAL1 deletion play a crucial role in preventing liver inflammation and fibrosis. Moreover, our studies challenge the current dogma that postulates a protective role for a functional circadian clock in the pathogenesis of metabolic diseases. We show that, while a functional circadian clock reportedly protects from liver pathology in healthy individuals, it can have detrimental effects on physiology when disease is already manifested.