For synchronous theranostic systems, there are two areas of focus. These are: excellent in vivo imaging and a multi-drug resistance (MDR) reversing ability for chemotherapy. Upconversion nanoparticles (UCNPs) exhibiting bright red emission in the "optical window in biological tissue (600-1100 nm)" could be a very useful candidate, although there have only been a few reports on UCNP-based conjugates with a MDR reversal ability explored for chemotherapy. Herein, we report an innovative theranostic system (D-UNT) via binding of an antitumor drug (DOX) and a MDR reversal agent (TPGS) to NaY(Mn)F4:Yb/Er UCNPs (UN) with synthetic optimized red emission and properties. The in vitro study demonstrated that the D-UNT was uptaken into drug-resistant MCF-7/ADR cells via caveolin dependent endocytosis and overcame P-gp mediated efflux. The cytotoxicity was significantly promoted to be much higher than that of free DOX. Accordingly, our D-UNT illustrates an enhanced reversal ability for chemotherapy. Our in vivo study further indicated that the D-UNT had excellent therapeutic efficacy against MDR tumors with minimal organ toxicity detected. In vivo deep-tissue imaging showed that the D-UNT accurately diagnosed MDR tumors at a 1.5 cm depth with high-contrast luminescent signals. Thus, the D-UNT is an effective theranostic system for the diagnosis and therapeutic treatment of MDR tumors. The present work opens new pathways to engineering powerful theranostic agents to simultaneously target, image and kill deep-tissue MDR tumor cells.