Scope: This study investigated the global transcriptional and metabolic changes occurring at multiple time points over 24 wk in response to a high‐fat diet (HFD). Methods and results: C57BL/6J mice were fed a HFD or normal diet (ND) over 24 wk. HFD‐fed mice developed early clinical indicators of obesity‐related co‐morbidities including fatty liver, insulin resistance, hyperglycemia and hypercholesterolemia. Time‐course microarray analysis at eight time points over 24 wk identified 332 HFD responsive genes as potential targets to counteract diet‐induced obesity (DIO) and related co‐morbidities. Glucose regulating enzyme activity and gene expression were altered early in the HFD‐fed mice. Fatty acid (FA) and triglyceride (TG) accumulation in combination with inflammatory changes appear to be likely candidates contributing to hepatic insulin resistance. Cidea seemed to be one of representative genes related to these changes. Conclusion: Global transcriptional and metabolic profiling across multiple time points in liver revealed potential targets for nutritional interventions to reverse DIO. In future, new approaches targeting HFD responsive genes and hepatic metabolism could help ameliorate the deleterious effects of an HFD and DIO‐related complication.