Drug-induced liver injury (DILI) has the potential to cause severe hepatitis and increases the risk of death which remains unresolved in current medical practice. During DILI, the H2O2 level is upregulated in the liver. Conventional blood tests fail to offer early and real-time visualization of DILI in vivo. Here we report a smart persistent luminescent approach to evaluate DILI in vivo using persistent luminescence nanoprobes which are conjugated with single-stranded DNA containing Ferrocene (Fc). Upon injection, these nanoprobes mainly accumulate in the liver and the persistent luminescence of nanoprobes remains suppressed owing to energy transfer to the ferrocene. The presence of H2O2 during DILI initiates the Fenton reaction to induce cleavage of DNA chains, and the ferrocene dissociates from the probes, leading to fast restoration of the persistent luminescence. The DILI imaging results revealed a signal-to-noise ratio of 20.9, approximately 10 h earlier than the serum-based detection methods. With its exceptional sensitivity, high signal-to-noise ratio, and real-time imaging capabilities, this smart persistent luminescent approach holds great promise for the early diagnosis of DILI.