Foodborne pathogenic bacteria form biofilms that are highly resistant, making them difficult to eradicate using conventional antimicrobial methods. To elucidate the efficacy and mechanism of Curcumin@ZIF-8 composite (CCM@ZIF-8) against Staphylococcus aureus (S. aureus) and its biofilms, CCM@ZIF-8 was synthesized via various methods. Materials with optimal performance were selected through BET and SEM analysis, and the inhibitory mechanism against S. aureus and its biofilms was investigated using transcriptomic technology. It was indicated that CCM@ZIF-8-RT-1S, synthesized via the one-step room-temperature method, possessed optimal loading capacity and pore structure. Outstanding antibacterial (76.34%) and biofilm removal (71.46%) activities against S. aureus were observed. A total of 1,267 differentially expressed genes (DEGs) were identified through transcriptome analysis, which were found to be significantly enriched in oxidative phosphorylation pathways by GO and KEGG analyses. The expression levels of genes encoding key enzymes in the electron transport chain (sdh, qox, cyoE) and the ATP synthase operon were consistently and significantly down-regulated. Furthermore, partial genes of the SrrAB two-component system and cidA were also down-regulated. It was demonstrated that the respiratory chain function, ATP synthesis capacity, and environmental stress perception of S. aureus were impaired by CCM@ZIF-8, ultimately inhibiting bacterial and biofilm growth. Molecular inhibition targets were identified, providing theoretical support for the application of ZIF-8-based antimicrobial materials in controlling foodborne pathogenic biofilms.