Ten thiosemicarbazone ligands obtained by condensation of pyridine‐2‐carbaldehyde, quinoline‐2‐carbaldehyde, 2‐acetylpyridine, 2‐acetylquinoline, or corresponding 2‐pyridyl ketones with thiosemicarbazides RNHC(S)NHNH2 and R=CH3, C6H5 were prepared in good yield. The reaction of [PdCl2(cod)] with cod=1,5‐cyclooctadiene or K2[PtCl4] resulted in a total of 17 Pd(II) and Pt(II) complexes isolated in excellent purity, as demonstrated by 1H, 13C, and, where applicable, 195Pt NMR spectroscopy combined with CHNS analysis. The cytotoxicity of the title compounds was studied on four human glioblastoma cell lines (GaMG, U87, U138, and U343). The most active compound, with a Pd(II) metal centre, a 2‐quinolinyl ring, and methyl groups on both the proximal C and distal N atoms exhibited an EC50 value of 2.1 μM on the GaMG cell lines, thus being slightly more active than cisplatin (EC50 3.4 μM) and significantly more potent than temozolomide (EC50 67.1 μM). Surprisingly, the EC50 values were inversely correlated with the lipophilicity, as determined with the “shake‐flask method”, and decreased with the length of the alkyl substituents (C1>C8>C10). Correlation with the different structural motifs showed that for the most promising anticancer activity, a maximum of two aromatic rings (either quinolinyl or pyridyl plus phenyl) combined with one methyl group are favoured and the Pd(II) complexes are slightly more potent than their Pt(II) analogues.