This study evaluates the role of SIRT5 in non-small cell lung cancer (NSCLC) progression and explores the underlying mechanism. The expression and correlation of SIRT5 and FABP4 in lung cancer were analyzed by the GEPIA database. The expression levels of SIRT5 and FABP4 in NSCLC cells were measured by qRT-PCR and western blot. The effect of SIRT5 and FABP4 on NSCLC cell development was determined. The interaction between SIRT5 and FABP4 was analyzed by co-immunoprecipitation (Co-IP). Tumor mass and volume were measured in nude mice to study the effect on the growth of NSCLC transplanted tumors. GEPIA database analysis showed that SIRT5 was highly expressed, while FABP4 was lowly expressed in lung cancer, which was consistent with the detection results of SIRT5 and FABP4 expressions in NSCLC cell lines. The expression of SIRT5 was negatively correlated with FABP4. Transfection of sh-SIRT5 in NSCLC cells led to a decrease in NSCLC cell malignancy, which was counteracted by sh-FABP4 transfection. Western blot and Co-IP showed that SIRT5 reduced FABP4 expression by inducting the deacetylation of FABP4. Nude mice in the sh-SIRT5 + sh-FABP4 group had significantly reduced tumor mass and volume compared with those in the sh-FABP4 group, while the tumor mass and volume in the sh-SIRT5 + sh-FABP4 group were increased in comparison to those in the sh-SIRT5 group. To conclude, collected evidence showed that SIRT5 promoted NSCLC cell development by reducing FABP4 acetylation level.