Abstract Conventional therapy to treat thrombi (blood clots) has significant limitations: i) inflammation; ii) bleeding side effects; iii) re‐embolisation, and iv) in situ thrombi that are not visible. Here it is reported that Cu2Ir nanoparticles (NPs) with a Cu‐coordinated tetraphenylporphyrin (TPP) core and cyclometalated Ir(C^N)2(N^N) substituents integrate long‐lived near‐infrared (NIR) chemiluminescence (CL) imaging, photothermal therapy (PTT) and photodynamic therapy (PDT) for thrombolysis, with antioxidant and anti‐inflammatory properties. Based on density functional theory calculations the chemiluminescent reaction site between TPP and peroxynitrite (ONOO−) is confirmed for the first time. The presence of the transition metal significantly improves the chemiluminescent properties of TPP. Upon specific activation by ONOO−, Cu2Ir NPs exhibited more than 30‐fold NIR CL intensity than TPP NPs, and the luminescence lasted for 60 min allowing for precise and long‐lasting dynamic tracking of thrombi. Cu2Ir NPs achieved non‐invasive safe thrombolytic therapy triggered by NIR irradiation at the signaling site. 72.3% blood reperfusion is obtained for nearly complete restoration of blood flow, and re‐embolism is prevented in a mouse carotid artery model. Furthermore, Cu2Ir NPs scavenged excess reactive oxygen/nitrogen species (RONS) and reduced inflammatory factors. Cu2Ir NPs hold promise as a single‐molecule strategy for diagnosing and treating diseases associated with thrombosis.