This study presents a series of iridium(III) half-sandwich complexes with π-expansive ligands, designed for efficient photodynamic therapy (PDT) in cancer treatment. The complexes, with formulas [Cp*Ir(CN)Cl] and [Cp*Ir(CN)L]BF4, were synthesized and characterized, showing remarkable phototoxicity indexes (PI > 2000) due to their ability to generate singlet oxygen (¹O₂). The π-expansion in the C^N ligands significantly increased the excited state lifetimes of the complexes, enhancing their efficiency in PDT. TD-DFT calculations confirmed that the π-expanded ligands contributed to a high ³ππ* character in the triplet excited state, leading to efficient ¹O₂ generation. The complexes exhibited strong cytotoxic effects on cancer cells, causing mitochondrial membrane depolarization, DNA cleavage, and lysosomal damage, ultimately leading to apoptosis and secondary necrosis. The most effective complexes, such as [Cp*IrL(pbpn)]⁺, showed exceptional PDT activity, with PI values up to 2000. These complexes demonstrated high solubility in polar solvents and good photostability. The study also evaluated the complexes' biological activity against A549 cancer cells, showing significant cell viability reduction under blue, green, and red light irradiation. The results indicate that the π-expanded ligands significantly enhance the PDT efficiency of iridium complexes, making them promising candidates for cancer treatment. The study highlights the importance of π-expansion in improving the photophysical properties of PDT agents, leading to more effective and targeted cancer therapies.This study presents a series of iridium(III) half-sandwich complexes with π-expansive ligands, designed for efficient photodynamic therapy (PDT) in cancer treatment. The complexes, with formulas [Cp*Ir(CN)Cl] and [Cp*Ir(CN)L]BF4, were synthesized and characterized, showing remarkable phototoxicity indexes (PI > 2000) due to their ability to generate singlet oxygen (¹O₂). The π-expansion in the C^N ligands significantly increased the excited state lifetimes of the complexes, enhancing their efficiency in PDT. TD-DFT calculations confirmed that the π-expanded ligands contributed to a high ³ππ* character in the triplet excited state, leading to efficient ¹O₂ generation. The complexes exhibited strong cytotoxic effects on cancer cells, causing mitochondrial membrane depolarization, DNA cleavage, and lysosomal damage, ultimately leading to apoptosis and secondary necrosis. The most effective complexes, such as [Cp*IrL(pbpn)]⁺, showed exceptional PDT activity, with PI values up to 2000. These complexes demonstrated high solubility in polar solvents and good photostability. The study also evaluated the complexes' biological activity against A549 cancer cells, showing significant cell viability reduction under blue, green, and red light irradiation. The results indicate that the π-expanded ligands significantly enhance the PDT efficiency of iridium complexes, making them promising candidates for cancer treatment. The study highlights the importance of π-expansion in improving the photophysical properties of PDT agents, leading to more effective and targeted cancer therapies.