Delayed neutrophil apoptosis has been proved to be closely associated with acute lung injury. A Bcl-2 inhibitor, venetoclax, can improve the clinical outcome of acute lung injury based on its pro-apoptotic effect. However, pulmonary delivery of free venetoclax is hindered by its water insolubility, which results in limited bioavailability and pharmacological effects. An amphipathic polymer-based nanodelivery system has been extensively used to improve the delivery of this insoluble drug and enhance its bioavailability. In this study, an amphiphilic poly(ethylene glycol) modified poly(α-lipoic acid) nanoparticle with an extended lung tissue-resident time was utilized to deliver venetoclax. Compared to free venetoclax, the nanoformulated venetoclax (Nf-venetoclax) presented better efficacy for acute lung injury through increasing neutrophil apoptosis in vivo. In addition, a stronger pro-apoptotic effect of Nf-venetoclax was also demonstrated in vitro. Our study provides encouraging evidence that Nf-venetoclax exhibits effective therapy for acute lung injury.