Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities.