The stress‐upregulated catecholamines‐activated β1‐ and β2‐adrenergic receptors (β1/2‐ARs) have been shown to accelerate the progression of cancers such as colorectal cancer (CRC). We investigated the underlying mechanism of the inhibition of β1/2‐ARs signaling for the treatment of CRC and elucidated the significance of β2‐AR expression in CRC in vitro and in clinical samples. The impacts of β1/2‐AR antagonists in CRC in vitro and CRC‐xenograft in vivo were examined. We found that repression of β2‐AR but not β1‐AR signaling selectively suppressed cell viability, induced G1‐phase cell cycle arrest, caused both intrinsic and extrinsic pathways‐mediated apoptosis of specific CRC cells and inhibited CRC‐xenograft growth in vivo. Moreover, the expression of β2‐AR was not consistent with the progression of CRC in vitro or in clinical samples. Our data evidence that the expression profiles, signaling, and blockage of β2‐AR have a unique pattern in CRC comparing to other cancers. β2‐AR antagonism selectively suppresses the growth of CRC accompanying active β2‐AR signaling, which potentially carries wild‐type KRAS, in vitro and in vivo via the inhibition of β2‐AR transactivated EFGR‐Akt/ERK1/2 signaling pathway. Thus, β2‐AR blockage might be a potential therapeutic strategy for combating the progressions of β2‐AR‐dependent CRC. J. Cell. Physiol. 231: 459–472, 2016. © 2015 Wiley Periodicals, Inc.