Four half‐sandwich iridiumIII (IrIII) triphenylamine or carbazole‐modified 2‐phenylpyridine (TPA/Cz‐PhPy) complexes ([(η5‐Cp*)Ir(C^N)Cl]) were synthesized and characterized. Compared with cisplatin, these complexes show higher activity to A549, HepG2 and HeLa cells, with the IC50 values changed from 2.5 ± 0.1 μM to 14.8 ± 2.6 μM. Additionally, complexes could effectively prevent the migration of cancer cells. IrIII TPA/Cz‐PhPy complexes could bind to protein and transport through serum protein, catalyze the oxidation of nicotinamide‐adenine dinucleotid (NADH) and induce the accumulation of reactive oxygen species, and eventually lead to apoptosis, which was also confirmed by flow cytometry. Moreover, prominent targeted fluorescence property confirmed that IrIII TPA/Cz‐PhPy complexes were involved in non‐energy dependent intracellular uptake mechanism, effectively accumulated in lysosomes and damage the integrity of acidic lysosomes, and eventually induce cell death. Above all, TPA/Cz‐appended half‐sandwich IrIII phenylpyridine complexes are promising anticancer agents with dual functions, including migration inhibition and lysosomal damage.