In this study, we linked classical organelle-targeting groups, such as triphenylphosphonium, pentafluorobenzene, and morpholine, to our previously reported potent monoiodo Aza-BODIPY photosensitizer (BDP-15). They were conveniently prepared and retained the advantages of Aza-BODIPY PS with intense NIR absorption, moderate quantum yield, potent photosensitizing efficiency, and good stability. The in vitro antitumor assessment indicated that mitochondria-targeting and lysosome-targeting groups were more effective than ER-targeting groups. Considering undesirable dark toxicity of triphenylphosphonium-modified PSs, compound 6 containing amide-linked morpholine possessed a favorable dark/phototoxicity ratio (>6900 for tumor cells) and was localized in lysosomes with Pearson's coefficient of 0.91 to Lyso-Tracker Green DND-26. 6 exhibited significantly increased intracellular ROS production and resulted in early/late apoptosis and necrosis to disrupt tumor cells. Moreover, in vivo antitumor efficacy exploration suggested that even under a slightly low dose of light (30 J/cm2) and single-time photoirradiation, 6 retarded tumor growth dramatically and displayed much better PDT activity over BDP-15 and Ce6.