Mitochondrial dysfunction is one of the key mechanisms for developing chronic kidney disease (CKD). Hyperoxaluria and nephrolithiasis are also associated with mitochondrial dysfunction. Increasing evidence has shown that caffeine, the main bioactive compound in coffee, exerts both anti-fibrotic and anti-lithogenic properties but with unclear mechanisms. Herein, we address the protective effect of caffeine against mitochondrial dysfunction during oxalate-induced epithelial-mesenchymal transition (EMT) in renal cells. Analyses revealed that oxalate successfully induced EMT in MDCK renal cells as evidenced by the increased expression of several EMT-related genes (i.e., Snai1, Fn1 and Acta2). Oxalate also suppressed cellular metabolic activity and intracellular ATP level, but increased reactive oxygen species (ROS). Additionally, oxalate reduced abundance of active mitochondria and induced mitochondrial fragmentation (fission). Furthermore, oxalate decreased mitochondrial biogenesis and content as evidenced by decreased expression of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), cytochrome c oxidase subunit 4 (COX4), and total mitochondrial proteins. Nonetheless, these oxalate-induced deteriorations in MDCK cells and their mitochondria were successfully hampered by caffeine. Knockdown of Snai1 gene by small interfering RNA (siRNA) completely abolished the effects of oxalate on suppression of cellular metabolic activity, intracellular ATP and abundance of active mitochondria, indicating that these oxalate-induced renal cell deteriorations were mediated through the Snai1 EMT-related gene. These data, at least in part, unveil the anti-fibrotic mechanism of caffeine during oxalate-induced EMT in renal cells by preserving mitochondrial biogenesis and function.