Ketosis is a common metabolic disease in high-yield dairy cows. Key genes affecting ketosis need to be further explored by new methods. The gene expression profiling and clinical data of GSE92398, GSE104079, and GSE4304 were obtained from the gene expression omnibus (GEO) database. Core modules and genes associated with RFI (residual feed intake) and ADF (alternate day fasting) were identified by weighted gene co-expression network analysis (WGCNA). Subsequently, the key genes related to ketosis and RFI were determined by protein-protein interaction (PPI) networks, ROC curves, functional enrichment, and differential expression analysis, respectively. The results showed that the genes of ACACA, ELOVL6 and XPO7 could be used as regulators of ketosis induced by low feed intake in dairy cows. At the same time, three genes (HRFI, STAT3 and IFNAR1) were retained as additional RFI biomarkers that could be considered. We identified three key factors as candidate genes and biomarkers of ketosis and RFI, respectively. These factors may provide a theoretical basis for targeted therapy of ketosis in dairy cows.