We report the coencapsulation of fluorocoxib Q (FQ) and chemocoxib A (CA) in micellar nanoparticles (FQ-CA-NPs) of a new PPS--POEGA diblock polymer, which exhibited a hydrodynamic diameter of 109.2 ± 4.1 nm and a zeta potential (ζ) of -1.59 ± 0.3 mV. The uptake of FQ-CA-NPs by 4T1 mouse mammary cancer cells and intracellular cargo release were assessed by fluorescence microscopy that resulted in increased fluorescence in 4T1 cells compared to cells pretreated with celecoxib. The viability of primary human mammary epithelial cells (HMECs) or 4T1 mouse mammary carcinoma cells treated with FQ-CA-NPs were assessed, which showed decreased growth of 4T1 breast cancer cells but showed no effect on the growth of primary human mammary epithelial cells (HMECs). Intravenous dosing of FQ-CA-NPs in mice enabled ROS-induced cargo (FQ and CA) release and fluorescence activation of FQ and resulted in increased fluorescence in breast tumors compared to the tumors of animals pretreated with tempol or celecoxib, and minimum fluorescence was detected in the tumors of animals treated with nothing or empty-NPs. In addition, tumor tissues from treated animals were analyzed by liquid chromatography-mass spectrometry (LC-MS)/MS, and identified increased levels of cargo delivery and retention in the tumor compared to tempol- or celecoxib-pretreated animal tumors. These and results confirmed the targeted delivery of loaded NPs followed by ROS-mediated cargo release and fluorescence activation for targeted visualization of drug delivery in breast tumors and CA-induced therapeutic effect in an tumor growth inhibition assay and an hematoxylin and eosin (H&E) staining of tumor tissues. Thus, coencapsulation of FQ and CA into polymeric micellar nanoparticles (FQ-CA-NPs) enabled their ROS-sensitive release followed by fluorescence activation and COX-2-dependent tumor targeting and retention in the visualization of CA delivery in solid breast tumors.