Epigenetic alterations have been reported to play critical roles in the development of colorectal cancer (CRC). However, the biological function of the lysine-specific histone demethylase 1B (LSD2/KDM1B) in CRC is not well understood. Therefore, we investigated the characteristics of LSD2 in CRC. We observed significant upregulation of LSD2 in CRC tissue compared to that in normal colorectal tissue. LSD2 promotes CRC cell proliferation and inhibits cell apoptosis through cell cycle regulation, promoting CRC progression both in vitro and in vivo. We found that LSD2 performs these functions by inhibiting the p53-p21-Rb pathway. Finally, we found that LSD2 directly binds to p53 and represses p53 expression via H3K4me2 demethylation at the p53 promoter. Our results revealed that LSD2 acts as an oncogene by binding and inhibiting p53 activity in CRC. Thus, LSD2 may be a new molecular target for CRC treatment.