Objective To investigate the promoting effect of histone deacetylase 1 (HDAC1) expression on insulin resistance (IR) in nonalcoholic fatty liver disease (NAFLD) cells by establishing an HepG2 cell model of high fat-induced NAFLD. Methods HepG2 cells were divided into control group, model group (OA), and inhibitor group (OA+pyroxamide [an HDAC1 inhibitor]). CCK-8 assay was used to plot the standard growth curve of HepG2 cells and screen out the optimal drug concentration and action time of OA and pyroxamide; oil red O staining was used to compare the accumulation of lipid droplets in cells; an automatic biochemical analyzer was used to analyze the content of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), and total cholesterol (TC) in cells; quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression levels of HDAC1 and insulin receptor substrate-1 (IRS-1) in cells. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups. Results OA treatment at a concentration of 0.25 mmol/L for 24 hours was the optimal concentration and duration of cell modeling, and treatment at a concentration of 20 μmol/L for 24 hours was the optimal administration concentration and duration of pyroxamide. Compared with the control group, the model group had significant increases in the content of ALT, AST, TG, and TC, and compared with the model group, the inhibitor group had significant reductions in the content of ALT, AST, TG, and TC (all P < 0.05). The model group had significantly higher mRNA and protein expression levels of HDAC1 than the control group, while the inhibitor group had significantly lower expression levels than the model group (all P < 0.05); the model group had significantly lower mRNA and protein expression levels of IRS-1 than the control group, while the inhibitor group had significantly higher expression levels than the model group (all P < 0.05). Conclusion HDAC1 participates in the development and progression of NAFLD by inhibiting the expression of IRS-1 molecule and promoting IR, and the HDAC1 inhibitor pyroxamide can exert a protective effect on the liver by alleviating IR.