Creatine has been linked to the development of kidney damage since 1998. However, uncertainties persist regarding the actual impact of creatine supplementation on individuals with kidney disease before supplementation or with pathological conditions that have an increased risk of developing kidney dysfunction. This study performed a comprehensive review of the literature and utilized bioinformatics tools to investigate the effects of creatine on renal tissue and function. Moreover, we identified 44 genes modulated explicitly in response to creatine exposure using the Comparative Toxicogenomics Database, including IGF1, SLC2A4, and various creatine kinase genes. The analysis revealed associations with metabolic processes such as amino acid metabolism, indicating a connection between creatine and tissue physiology. Gene expression analysis using the Genotype-Tissue Expression Portal highlighted tissue-specific expression patterns in kidney and pancreas tissues. Furthermore, the study explored creatine metabolism pathways and kinase regulation through biological databases and Gene Expression Omnibus data, shedding light on the potential regulatory roles of creatine in cellular processes during kidney diseases. Understanding the impact of the balance between the endogenous creatine synthesis and the creatine uptake, particularly the genes GATM, GAMT, SLC6A8 and IGF1, insights into molecular mechanisms underlying creatine's physiological effects on renal tissues. Overall, this work provides new insights into the molecular interactions and pathways influenced by creatine in renal function.