Abstract Aiming to create an innovative series of anti‐colorectal cancer agents, we designed in this work hybrid triarylmethane compounds. Three hybrid triarylmethanes and their corresponding N ‐oxide analogues were successfully synthesized using an efficient procedure that involved connecting two triarylmethane molecules, through mono‐, bi‐, and triethylene glycol fragments. In our pursuit to develop more soluble molecules, we synthesized a hybrid triarylmethane featuring a lysine‐based spacer through a convergent strategy involving 7 steps. All hybrid compounds were assessed for their antiproliferative activity on human HT‐29 and HCT116 colorectal cancer (CRC) cell lines. Three pyridine N ‐oxide analogs demonstrated notable antiproliferative potential among the set of tested compounds, with IC 50 values ranging from 18 to 24 μM on both human CRC cell lines analyzed. A cytotoxicity study conducted on murine fibroblasts revealed that these three active compounds were not toxic at the IC 50 values, indicating their suitability for further drug development. A docking study was conducted on two representative compounds, one for each series and protein kinase B (AKT) was identified as a potential target of their in anti‐cancer effects. A computational drug‐likeness study predicted favourable oral and intestinal absorption efficiency.