<p>Nanolithography involves transforming optical signals into nanostructures on a substrate through a photoresist layer. Metal-organic cluster (MOC) photoresists, which combine metal atoms with organic ligands, have emerged as innovative materials. Despite extensive investigations into functional ligands and metal complexes, the sensitivity of metal-organic nanocluster photoresists remains influenced by the largely unexplored effects of non-metallic groups in organic ligands. Here, a series of aromatic Zr-based nanoscale metal-organic cluster photoresists (Zr-XBA) with non-metallic groups (methyl, fluorine, iodine) were synthesized to investigate their impact on sensitivity for nanoscale patterning. Zr-mMeBA modified with electron-donating group methyl showed higher sensitivity, which contributed to the development of high-performance photoresists. The results obtained through DFT simulations were consistent with the experimental results, demonstrating that Zr-mMeBA with a large HOMO-LUMO gap and weak electrophilic characteristics exhibited the best stability and the highest sensitivity. This research advances the understanding of MOC photoresists’ patterning mechanisms and lays the groundwork for designing new high-performance photoresists.</p>