Persistent luminescence without excitation light and tissue autofluorescence interference holds great promise for in vivo imaging and sensing. However, the availability of persistence luminescence materials is largely limited by potential toxicity, instability, short-wavelength emissions, and poor clinical potential for currently available ones. Here we report a series of porphyrin derivatives with near-infrared (NIR) persistence luminescence for image-guided cancer surgery and drug screening. These porphyrin derivatives showed NIR persistence luminescence over 760 nm after cessation of excitation light or upon interaction with peroxynitrite (ONOO-), and a plausible mechanism of ordered oxidation of vinylene bond is proposed. Through molecular engineering with adaptive peptides bearing the functions of β-sheet-formatting and cancer cell targeting, the resultant Ppa-FFGYSA supermolecular probe showed enhanced photoacoustic and persistence luminescence signals, facilitating preoperative photoacoustic tumor identification and intraoperative persistence luminescence image-guided tumor resection with outperformed signal-to-background ratio. In addition, the activated persistence luminescence in recognition of ONOO- also permits the specific monitoring of neutrophil infiltration and screening of immunogenic cell death (ICD) drugs with high sensitivity and specificity.