Accumulating evidence has indicated that sirtuins are key components of diverse physiological processes, including metabolism and aging. Sirtuins confer protection from a wide array of metabolic and age-related diseases, such as cancer, cardiovascular and neurodegenerative diseases. Recent studies have also suggested that sirtuins regulate autophagy, a protective cellular process for homeostatic maintenance in response to environmental stresses. Here, we describe various biological and pathophysiological processes regulated by sirtuin-mediated autophagy, focusing on cancer, heart, and liver diseases, as well as stem cell biology. This review also emphasizes key molecular mechanisms by which sirtuins regulate autophagy. Finally, we discuss novel insights into how new therapeutics targeting sirtuin and autophagy may potentially lead to effective strategies to combat aging and aging-related diseases.