Diabetic kidney disease (DKD) remains a prevalent complication of diabetes mellitus and a leading cause of end-stage renal disease. A growing body of evidence highlights the central role of the thioredoxin-interacting protein (TXNIP)-mTOR-autophagy axis in the pathogenesis of DKD. Chronic hyperglycemia significantly induces TXNIP expression, triggering oxidative stress, inflammasome activation, and mitochondrial dysfunction in renal cells. TXNIP directly promotes activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which consequently impairs autophagic flux, leading to accumulation of damaged organelles and proteins, cellular hypertrophy, and fibrosis. Restoration of autophagy via inhibition of TXNIP or mTOR signaling pathways alleviates these pathological changes in various DKD models. Specifically, genetic or pharmacological suppression of TXNIP attenuates oxidative injury, reduces inflammasome activation, and restores autophagic activity. Similarly, mTOR inhibitors such as rapamycin have demonstrated substantial renoprotective effects through reactivation of autophagy and reduction of renal fibrosis. Furthermore, combined targeting of TXNIP and mTOR presents a promising therapeutic strategy that may synergistically restore autophagic homeostasis with reduced side effects. This review synthesizes recent mechanistic insights into the interplay between TXNIP, mTOR signaling, and autophagy dysregulation in DKD and discusses potential therapeutic interventions. Ultimately, understanding and therapeutically targeting the TXNIP-mTOR-autophagy axis could offer new opportunities for effective clinical management of diabetic kidney disease.