BackgroundModern lifestyle increasingly deprives people from sleep to different degrees. Long-term sleep deprivation will facilitate body’s pathological behaviors, such as lethargy, depression, and anorexia.ObjectiveThis study is an investigation into the mechanism of hydrolyzed seawater pearl tablet in treating chronic sleep deprivation mice model.MethodsThe chronic sleep deprivation model was established involving C57BL/6mice; the body weight, behavioral characteristics, hippocampal structure, oxidative stress, apoptosis-related protein expression, and intestinal bacteria in mice were assessed to characterise hydrolyzed seawater pearl tablet.ResultsHydrolyzed seawater pearl tablet significantly accelerated body weight, open field test score, and sugar water preference rate (P< 0.05), alleviated the structural damage of hippocampus, reduced the content of MDA (P< 0.05), Bax protein expression, increased the content of GSH (P< 0.05), the activities of SOD, GSH-Px, and Bcl-2 protein expression in the hippocampus, increased theEscherichia coli, Bacteroides, Bifidobacterium and Lactobacillus (P< 0.05), which are beneficial bacteria in the intestine, in chronic sleep deprivation mice, and reduced the amount of Clostridium perfringens (P< 0.05), which are harmful bacteria in the intestine.ConclusionHydrolyzed seawater pearl tablet can improve the depression-like mental state of mice caused by chronic sleep deprivation. The mechanism involves improving the antioxidant activity of the hippocampus to eliminate the excessive ROS, which inhibits cell apoptosis and alleviates tissue structure damage. Meanwhile, it may also be involved in adjusting the microbiota level and improving the mental and behavioral activities of chronic sleep deprivation mice through the intestine-brain axis.