Background/Objectives: The global high prevalence of cardiovascular diseases (CVDs) is attributed to the high prevalence of obesity and metabolic syndrome. However, the impact of a high-fat diet (HFD) on the expression of genes in cardiac tissue remains poorly understood. Methods: A thorough literature search was performed using PubMed, Scopus, EBSCOhost, and ScienceDirect databases. The Medical Subject Heading (MeSH) terms such as “high-fat diet”, “gene expression” and “cardiac tissue” were used as the keywords in all fields. Results: A total of 1608 studies were retrieved, and only in vivo experimental studies to identify cardiac tissues differentially expressed genes (DEGs) or proteins (DEPs) in rodents fed with HFD were selected. After screening, 14 studies were selected, 159 DEGs and DEPs were extracted from the data and further analysis was conducted employing DAVID, STRING, and Cytoscape 3.10.3 software. A protein–protein interaction (PPI) network revealed a total of 159 genes and proteins from the selected DEGs containing 100 nodes and 292 edges with a PPI enrichment p-value of < 1.0 × 10⁻¹⁶ and an average local clustering coefficient of 0.447 with an average node degree of 5.84. Six significant clusters with high intermolecular interactions from the protein–protein interaction (PPI) network complex reveal significant molecular pathways, including the glucose metabolic process, fatty acid metabolic process, and inflammatory response (p < 0.05). Conclusions: The identification of the critical link between obesity and HFD-induced CVDs in cardiac tissue highlights the need for a deeper understanding of the molecular mechanisms controlling gene expression in cardiac tissue.