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This study investigates topoisomerase I and II enzyme inhibition by novel Pd(II) complexes. TSC represents the chelating ligand thiosemicarbazone, which is modified at its 4(N)‐nitrogen terminal position with substituents such as C2H5, CH3, and H. PR3 represents the triphenylphosphine ligand, with positional variations including para substituents H, F, OCH3, and CH3. The aim is to establish a correlation between these molecular variations and cytotoxicity. In particular, the compounds show promising cytotoxicity against MDA‐MB‐231 and A549 tumor cell lines, especially those with H substitution at the terminal position 4(N) of TSC and H and F in the triphenylphosphine. The results suggest that a smaller molecular volume of ligand substituents may enhance the cytotoxic effects. The inhibitory potential of the complexes against DNA topoisomerase enzymes was investigated. The IC₅₀ values of the most promising complexes strongly inhibit TOPOIIα and TOPOIβ, suggesting these enzymes as primary targets. These complexes exhibited significantly lower IC₅₀ values (4.32–4.88 μM) compared to cisplatin (10.2 μM) against MDA‐MB‐231 cells, indicating a distinct mode of action. However, it is noteworthy that the complexes did not inhibit the action of DNA topoisomerase IIβ, suggesting selectivity against specific isoforms of DNA topoisomerase II that act as catalytic inhibitors. [ABSTRACT FROM AUTHOR]