Objective: To evaluate the efficacy of palbociclib alone or in combination with the EGFR inhibitor erlotinib in the treatment of colorectal cancer (CRC). Methods: Alamar bule method and clone formation assay were used to detect the effects of palbociclib alone or in combination with erlotinib on the proliferation of CRC cell lines. Cell cycle distribution was determined by DNA content. Cell senescence and ROS accumulation were detected by β-galactosidase and DCFH-DA staining. The expression levels of related proteins were analyzed by Western blot and their clinical efficacies were evaluated in CRC patient-derived xenograft (PDX) models. Results: Palbociclib inhibits CRC cell proliferation, induce G1 cell arrest, cell senescence and intracellular ROS accumulation effectively. Combination of palbociclib and erlotinib exhibits synergistic effects on CRC, and erlotinib further enhances the multiple inhibitory effects and multi-signaling pathway inhibition of palbociclib on CRC. Synergistic inhibition was also shown in CRC PDX models.