Malate dehydrogenase 1 (MDH1) and isocitrate dehydrogenase 1 (IDH1) are two crucial enzymes in the process of energy metabolism. MDH1 plays a crucial role in the malate-aspartate shuttle in the cytoplasm by utilizing the coenzyme NAD/NADH to catalyze the interconversion of malate and oxaloacetate. IDH1 utilizes the coenzyme NADP/NADPH to facilitate the reciprocal transformation between isocitrate and α-ketoglutarate and plays a significant role in the metabolic processes of carbohydrates, lipids, and proteins in the liver. MDH1 and IDH1, along with their posttranslational modifications such as methylation and acetylation can influence the development of many diseases. This article reviews the function of MDH1, IDH1, and their posttranslational changes in various illnesses, aiming to offer new perspectives on disease diagnosis and therapy.