Optical　imaging　in　the　second　near-infrared　(NIR-II,　900–1700 nm)　window　has　been　extensively　investigated　for　bioimaging.　However,　a　strong　autofluorescence　background　from　real-time　excitation　light　significantly　reduces　the　images’　quality　of　NIR-II　fluorescence　(FL)　imaging.　To　resolve　this　issue,　a　NIR-II　self-luminous　small　molecule　(CLPD)　based　on　bioluminescence　(BL)　resonance　energy　transfer　(BRET)　mechanism　is　first　developed.　The　reactive　oxygen　species　(ROS)　can　trigger　NIR-II　BL　and　reduce　the　NIR-II　FL　signals　of　the　CLPD　simultaneously,　enabling　ROS-correlated　ratiometric　BL/FL　imaging.　CLPD　is　used　for　high-contrast　NIR-II　BL　imaging　of　osteoarthritis　as　well　as　guiding　the　treatment　process　by　ratiometric　BL/FL　imaging.　Moreover,　CLPD　is　applied　for　NIR-II　BL　imaging　of　tumor　triggered　by　the　generated　ROS　during　PDT.　A　correlation　between　the　ratiometric　NIR-II　BL/FL　signal　and　tumor　size　is　constructed,　providing　a　trustworthy　tool　for　early　assessment　of　PDT　effect.　Overall,　this　study　presents　a　novel　NIR-II　self-luminous　small　molecular　probe　for　in　vivo　imaging　and　provides　a　strategy　for　design　a　self-evaluation　system　of　therapeutic　effect.　©　2022　Wiley-VCH　GmbH.