The prevalence of sleep deprivation is increasing worldwide. Despite the vital roles that the liver plays in metabolism and immune response, hepatic dysfunctions in acute sleep deprivation (ASD) and chronic sleep deprivation (CSD) remain underexplored. Additionally, the effects of the newly developed chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (TAK), were evaluated as a potential therapeutic chemical for mitigating SD-induced hepatic damage. A modified multi-platform method was employed to prepare animal models of 72 h ASD and 21-day CSD in rats. TAK (50 mg/kg/day) was administered through irrigation starting one week before the experiment and continuing until the end. ASD triggered hepatic lipid accumulation and inflammation, whereas CSD resulted in pathological portal area expansion and fibrosis, with comparatively fewer disturbances in liver metabolism and inflammation. TAK effectively alleviated ASD-induced disruptions in glycogen synthesis via PI3K/AKT/GSK3/GYS2 pathways, abnormal lipid accumulation via SREBP1/FASN/ACC, liver inflammation by balancing M1 and M2 macrophages, and liver fibrosis induced by ASD/CSD. This study provides valuable insights into the different mechanisms of liver damage induced by severe ASD and mild CSD. Additionally, TAK has been proposed as a potential therapeutic strategy for ultimate SD-related hepatic complications.