New series of some transition metal complexes was prepared from the novel H2Enro-o-phdn Schiff base: N,N0-phenylene (bis1-cyclopropyl-7-(4-ethylpiperazin-1-yl)- 6-fluoro-1,4-dihydroquinoline-3-carboxylic acid). The ligands and its chelates were investigated by elemental, spectroscopic, and thermal data analysis. The ligand chelates as anion tetradentate (N2O2) with metal ions forming distorted octahedral structure. The thermal properties of compounds were examined using TG equipment. It was found that La(III) and Zr(IV) chelates showed the robust anticancer efficacy against “CT26” colon cancer cells compared with the positive control “cisplatin.” This was further validated by western blotting analysis, to assess the impact of H2Enro-o-phdn complexes on the level of P53. In response of treatment with the complexes, overexpression of this pro-apoptotic protein was obviously detected in “CT26” colon cancer cells, thereby may contribute to inducing the apoptosis in cancer cells. Also, it was observed as the P53 protein levels will increase concomitantly with the increase the metal–ligand covalency. Thus, H2Enro-o-phdn in addition to its chelates could be in the development of P53-based colon cancer medications.