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This study aimed to explore the candidate genes associated with simple steatosis (SS) using integrated bioinformatics analysis. Data in GSE89632 were used to identify differentially expressed genes (DEGs) between SS and healthy controls (HC). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs was conducted. Protein–protein interactions (PPI) network and transcription factor (TF)-gene network were constructed, followed by pathway analysis. Drug-gene interactions were also predicted. Finally, the expression level of hub genes was verified using GSE126848 and quantitative real-time PCR (qRT-PCR). A total of 418 (139 up-regulated and 279 down-regulated) DEGs were identified between SS and HC groups. PPI analysis revealed that FOS, MYC, IL1B, and EGR1 might be considered as hub genes. Pathway analysis showed that these genes were mainly involved in TNF signaling pathway. Drug-gene interaction analysis identified six gene targets (PTGS2, IL1B, MMP9, CCL2, JUN, and IL6) and 38 small molecules. Further experimental verification confirmed that the expression level of FOS, MYC, IL1B, and EGR1 was significantly down-regulated in the SS samples. In conclusion, these data may provide new insights into the pathogenesis and treatment of SS. These hub genes and candidate drugs may improve the individualized diagnosis and treatment of SS.