In the present study, we investigated the role of salt-induced kinase 1 (SIK1), a serine/threonine kinase protein, in colorectal cancer (CRC). Despite the reported association of SIK1 with tumor malignancy suppression in various cancers, limited research has been conducted on its function in CRC. Our findings revealed that SIK1 expression was low in CRC cells. The results of a KEGG pathway analysis showed a strong association between SIK1 and the TGF-β signaling pathway. In addition, a coimmunoprecipitation assay validated the interaction between SIK1 and Smad7. Our data indicate that SIK1 inhibited the phosphorylation of Smad2, a critical molecule in the Smad-related TGF-β pathway, and downstream target genes of the TGF-β pathway. Furthermore, SIK1 was found to inhibit indicators of epithelial-mesenchymal transition (EMT) and reverse oxaliplatin resistance in CRC. Additionally, SIK1 reduced cell migration and invasion. Our results suggest that the inhibitory effect of SIK1 on the TGF-β pathway contributes to the suppression of metastasis and oxaliplatin chemoresistance in CRC. However, this effect was reversed by galunisertib (LY2157299). In conclusion, our findings provide novel insights into the role of SIK1 in the regulation of the TGF-β pathway in CRC, suggesting its potential as a therapeutic target for the treatment of CRC. Further studies are required to fully characterize the mechanism underlying these observations and to validate these findings in animal models.© The author(s).