Real-time and objective feedback of therapeutic efficacies would be of great value for tumor treatment. Here, we report a smart Ag2S QD-based theranostic nanoplatform (DOX@PEG-Ag2S) obtained by loading the anti-cancer drug doxorubicin (DOX) into polyethylene glycol-coated silver sulfide quantum dots (PEG-Ag2S QDs) through hydrophobic-hydrophobic interactions, which exhibited high drug loading capability (93 wt.% of DOX to Ag2S QDs), long circulation in blood (t (1/2) = 10.3 h), and high passive tumor-targeting efficiency (8.9% ID/gram) in living mice where % ID/gram reflects the probe concentration in terms of the percentage of the injected dose (ID) per gram of tissue. After targeting the tumor tissue, DOX from PEG-Ag2S cargoes was selectively and rapidly released into cancer cells, giving rise to a significant tumor inhibition. Owing to the deep tissue penetration and high spatio-temporal resolution of Ag2S QDs fluorescence in the second near-infrared window (NIR-II), the DOX@PEG-Ag2S enabled real-time in vivo reading of the drug targeting process and therapeutic efficacy. We expect that such a novel theranostic nanoplatform, DOX@PEG-Ag2S, with integrated drug delivery, therapy and assessment functionalities, will be highly useful for personalized treatments of tumors.