Zinc phthalocyanine (ZnPc), a promising second-generation photosensitizer, suffers from decreased quantum yield of singlet oxygen due to poor water solubility and prone-to-aggregation nature in both physiological environment and solid matrix. To address this issue, in this work we reported a simple ligand-assisted reprecipitation method to prepare aggregation-free ZnPc-doped nanoparticles (NPs). Specifically, a short-chain ligand hexylamine was introduced to coordinate with ZnPc during reprecipitation, so that to alleviate ZnPc aggregation in the polymeric nanomatrix. As a consequence, the as-prepared ZnPc-loaded NPs with an optimal loading content of 4 wt.% acquired a high singlet oxygen quantum yield (ΦΔ) of 0.5, which was comparable to that of ZnPc monomer (ΦΔ = 0.55). Moreover, 10 wt.% ZnPc-loaded NPs could still retain a singlet oxygen quantum yield of 0.38. Taking advantage of the aggregation-free nano-photosensitizers, efficient photodynamic therapy effect was achieved on HeLa cells upon 660-nm photo-irradiation with an ultra-low light dose (1.8 J/cm2). This study not only presented a high efficient ZnPc-based nano-photosensitizer, but also proposed a new strategy to reduce the aggregation of metal complex in solid matrix through ligand coordination.