Aldo-keto reductase family 1 member B1 (AKR1B1) was historically characterized as the first and generally rate-limiting enzyme of the polyol pathway and, consequently, was primarily implicated in the pathogenesis of diabetic complications. Recent advances, however, have repositioned AKR1B1 as a pleiotropic signaling hub whose biological functions extend far beyond glucose metabolism. This review systematically integrates the complex regulatory network governing AKR1B1, including transcriptional control by tumor protein p53 (p53) and nuclear factor erythroid 2-related factor 2 (Nrf2), and its dual functionality as both a metabolic enzyme and a non-catalytic signaling scaffold. We elucidate its role in orchestrating cell fate by bi-directionally regulating apoptosis and ferroptosis, driving epithelial-mesenchymal transition (EMT), and fueling metabolic reprogramming via endogenous fructose production. Furthermore, we highlight its pathological significance in human diseases, ranging from gastric cancer and glioblastoma to aortic valve calcification. Finally, we evaluate the therapeutic prospect of targeting AKR1B1, emphasizing the need for novel strategies that address both its enzymatic activity and protein-protein interactions.