Human neutrophils are the most abundant circulating leukocytes and contribute to acute and chronic inflammatory disorders. Neutrophil apoptosis is programed cell death to maintain immune homeostasis, but inflammatory responses to infections or tissue injury disrupt neutrophil death program, leading to many diseases. Precise control of neutrophil apoptosis may resolve inflammation to return immune homeostasis. Here, we report a method in which doxorubicin (DOX)–conjugated protein nanoparticles (NPs) can in situ selectively target inflammatory neutrophils for intracellular delivery of DOX that induces neutrophil apoptosis. We showed that neutrophil uptake of NPs required their activation and was highly selective. DOX release was triggered by acidic environments in neutrophils, subsequently inhibiting neutrophil transmigration and inflammatory responses. In two disease models, DOX-conjugated NPs notably increased mouse survival in sepsis and prevented brain damage in cerebral ischemia/reperfusion, but the NPs did not suppress systemic immunity. Our studies offer a promising strategy to treat inflammatory diseases.