Identification of new therapeutic targets may improve the survival rate of patients with colorectal cancer (CRC). Recent studies have suggested that the level of phosphodiesterase 4B (PDE4B) is elevated in fatal/refractory diffuse large B-cell lymphoma (DLBCL), and therapeutic efficacy of a PDE4 inhibitor in B-cell lymphoma has been successfully tested in clinical settings. Here, we show that PDE4B is a potential therapeutic target in CRC. Treatment with forskolin, an activator of adenylyl cyclase (AC), increased intracellular cyclic AMP (cAMP) levels in PDE4B-low, but not PDE4B-high cells, indicating that PDE4B was a major regulator of cAMP levels in CRC cells. Furthermore, cAMP modulated the activities of AKT and AMPK in a PDE4B-dependent manner, which was associated with a marked decrease in mTOR-Myc signals and oncogenic properties of CRC cells such as anchorage-independent growth and colony formation. We found that the Myc proto-oncogene was a crucial downstream target of the AKT/mTOR and AMPK/mTOR signals that mediated cAMP-induced anti-tumor effect. A natural polyphenol resveratrol that was reported to have PDE4 inhibitory effects also showed tumor suppressive effects by inhibiting the mTOR-Myc axis. Intriguingly, we identified Myc as a transcriptional activator of PDE4B in CRC cells, which maintains the intracellular cAMP levels low and promotes cell survival. These data suggest that cAMP/PDE4B signals play a significant role in regulating the malignant phenotype of CRC cells and targeting of PDE4B should be actively pursued.