One of the main zeitgebers in the digestive system is food intake, however little is known about sex-specific differences in food-driven circadian regulation. Thus, we placed male and female C57Bl/6 mice on time-restricted feeding (TRF), limiting food intake to 8 hours per 24-hour period. TRF was started either at dark (ZT12) or light (ZT0) onset and continued for 28 days, with or without additional 4h forward shift on day 15 of entrainment. Changes in weight gain, fasting blood glucose, intestinal transepithelial resistance (TEER) and nutrient metabolism-related gene expression were assessed in multiple digestive organs at various timepoints.Long-term time-restricted night feeding led to the highest weight gain in females, but the lowest weight gain in males, while improving TEER in both sexes. However, it also led to a disappearance of diurnal rhythmicity in expression of several hepatic genes. Physiological responses in shifted night-fed females were largely indistinguishable from the night-fed group, whilst in males shifted night feeding led to an increase in weight gain and a decrease of fasting plasma glucose. Food intake during late dark phase also acted as a powerful zeitgeber for genes encoding regulators of nutrient intake and metabolism in liver and duodenum. Surprisingly, food intake during lights-on phase caused only minor changes in physiological responses. However, it did lead to an overall downregulation of gene expression in liver and an upregulation in stomach and duodenum, and to flattening of the diurnal responses. Placing food intake in the late lights-on phase negatively affected glucose metabolism and the integrity of the intestinal epithelium, causing an increased fasting glucose level in both sexes and low ileal TEER in male mice. It had similar effects on overall gene expression in liver and stomach as day feeding, however in duodenum it acted as a potent zeitgeber.These results demonstrate that adjustment to food intake time in mice is highly sex- and organ-specific. In our model, TRF was not able to achieve full diurnal rhythm synchronization across the digestive system. Instead, we observed that the same food intake time might be a strong zeitgeber in one organ, and a rhythm disruptor in another.