Pancreatic beta-cell death has been established as a critical mediator in the progression of type 1 and type 2 diabetes mellitus. Beta-cell death is associated with exacerbating hyperglycemia and insulin resistance and paves the way for the progression of DM and its complications. Apoptosis has been considered the primary mechanism of beta-cell death in diabetes. However, recent pieces of evidence have implicated the substantial involvement of several other novel modes of cell death, including autophagy, pyroptosis, necroptosis, and ferroptosis. These distinct mechanisms are characterized by their unique biochemical features and often precipitate damage through the induction of cellular stressors, including endoplasmic reticulum stress, oxidative stress, and inflammation. Experimental studies were identified from PubMed literature on different modes of beta cell death during the onset of diabetes mellitus. This review summarizes current knowledge on the crucial pathways implicated in pancreatic beta cell death. The article also focuses on applying natural compounds as potential treatment strategies in inhibiting these cell death pathways.