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Hepatocyte stress signaling has been established to alter glucose metabolism and impair systemic glucose homeostasis. In contrast, the role of stress defenses in the control of glucose homeostasis is less understood. Nuclear factor erythroid 2 related factor-1 (NRF1) and −2 (NRF2) are transcription factors that promote stress defense and can exert hepatocyte stress defense programming via complementary gene regulation. To identify whether there are independent or complementary roles of these factors in hepatocytes on glucose homeostasis, we investigated the effect of adult-onset, hepatocyte-specific deletion of NRF1, NRF2, or both on glycemia in mice fed 1–3 weeks with a mildly stressful diet enriched with fat, fructose, and cholesterol. Compared to respective control, NRF1 deficiency and combined deficiency reduced glycemia, in some cases resulting in hypoglycemia, whereas there was no effect of NRF2 deficiency. However, reduced glycemia in NRF1 deficiency did not occur in the leptin-deficient mouse model of obesity and diabetes, suggesting hepatocyte NRF1 support defenses that counteract hypoglycemia but does not promote hyperglycemia. Consistent with this, NRF1 deficiency was associated with reduced liver glycogen and glycogen synthase expression as well as marked alteration to circulating level of glycemia-influencing hormones, growth hormone and insulin-like growth factor-1 (IGF1). Overall, we identify a role for hepatocyte NRF1 in modulating glucose homeostasis, which may be linked to liver glycogen storage and the growth hormone/IGF1 axis. • Hepatocyte NRF1 deficiency lowers glycemia, but does not promote hyperglycemia. • In contrast, hepatocyte NRF2 deficiency has no effect on glycemia. • Hepatocyte NRF1 promotes glycogen synthase expression and glycogen storage. • Hepatocyte NRF1 promotes the growth hormone/insulin-like growth factor 1 axis. [ABSTRACT FROM AUTHOR]