Targeting DNA repair mechanisms, particularly PARP-1 inhibition, has emerged as a promising strategy for developing anticancer therapies. we designed and synthesized two 2-thiazolecarboxaldehyde thiosemicarbazone palladium(II) complexes (C1 and C2), and evaluated their anti-cancer activities. These Pd(II) complexes exhibited potent PARP-1 enzyme inhibition and demonstrated considerable antiproliferative activity against various cancer cell lines. In vivo studies using the A549 tumor xenograft model revealed that C2 effectively suppressed tumor growth and exhibited minimal systemic toxicity. Mechanistically, C2 induced A549 cell death through multiple pathways: cell cycle arrest, elevated intracellular reactive oxygen species (ROS) levels, DNA damage induction, exacerbated DNA double-strand breakage via PARP-1 inhibition, mitochondrial membrane potential reduction, and ultimately apoptosis. These findings provide a new design strategy for developing safe and highly effective PARP-1 inhibitors.