Background: We aimed to investigate the possible effect of statins on important genes/proteins involved in foam cell formation. Methods: The gene expression profile of the GSE9874, GSE54666, and GSE7138 from the Omnibus database were used to identify genes involved in foam cell formation. The protein–protein interaction (PPI) network and MCODE analysis of the intersection of three databases were analyzed. We used molecular docking analysis to investigate the possible interaction of different statins with the overexpressed hub genes obtained from PPI analysis. Results: The intersection among the three datasets showed 54 upregulated and 26 down-regulated genes. The most critical overexpressed genes/proteins obtained as hub genes included: G6PD, NPC1, ABCA1, ABCG1, PGD, PLIN2, PPAP2B, and TXNRD1 based on PPI analysis. Functional enrichment analysis of 81 intersection DEGs at the biological process level focusing on the cholesterol metabolic process, secondary alcohol biosynthetic process and the cholesterol biosynthetic process. Under cellular components, the analysis confirmed that these 81 intersection DEGs were mainly applied in endoplasmic reticulum membrane, lysosome and lytic vacuole. The molecular functions were identified as sterol binding, oxidoreductase activity and NADP binding. The molecular docking showed that all statins appear to affect important protein targets overexpressed in foam cell formation. However, lipophilic statins, especially pitavastatin and lovastatin, had a greater effect than hydrophilic statins. The most significant protein target of all the overexpressed genes interacting with all statin types was ABCA1. Conclusion: The effect of lipophilic statins was shown for several critical proteins in foam cell formation.