Autophagy is a dynamic intracellular process of protein degradation, which is mostly triggered by nutrient deprivation. This process initiates with the formation of autophagosomes, which they capture cytosolic material that is then degraded upon fusion with the lysosome. Several factors have been found to be associated with autophagy modulation, of which extracellular matrix (ECM) components has attracted the attention of recent studies. Osteopontin (OPN) is an important extracellular matrix component that has been detected in a wide range of tumor cells, and is involved in cancer cell invasion and metastasis. Recently, a number of studies have focused on the relationship of OPN with autophagy, by delineating the intracellular signaling pathways that connect OPN to the autophagy process. We will summarize signaling pathways and cell surface receptors, through which OPN regulates the process of autophagy.