•Role of ER stress and autophagy in the pathogenesis of diabetes.•ER stress and autophagy crucial in diabetic microvascular complications pathogenesis.•Modulation of ER stress and autophagy as novel strategy against diabetic complications.•ER stress and autophagy interplay in diabetic microvascular complications. Endoplasmic reticulum (ER) homeostasis orchestrates the folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, thus governing cellular functions. Alterations in ER homeostasis result in the activation of signaling pathways, such as the unfolded protein response (UPR), to regain ER homeostasis. Nevertheless, failure of UPR leads to activation of autophagy-mediated cell death. Several recent studies emphasized the association of the ER stress (ERS) response with the initiation and progression of diabetes. In this review, we highlight the contribution of the ERS response, such as UPR and autophagy, in the initiation and progression of diabetes and associated microvascular complications, including diabetic nephropathy (DN), retinopathy, and neuropathy, in various experimental models, as well as in humans. We highlight the ERS as a putative therapeutic target for the treatment of diabetic microvascular complications and, thus, the urgent need for the development of improved synthetic and natural inhibitors of ERS. Endoplasmic reticulum stress, autophagy, and their interplay are crucial in the development of diabetes and associated microvascular complications, requiring further investigations.