The emergence of multidrug resistance (MDR) is the leading cause of mortality in patients with breast cancer. Overexpressed P-glycoprotein (P-gp) that can pump out chemotherapeutics from multidrug-resistant cancer cells is the main cause of chemotherapy failure. P-gp inhibitors are hence increasingly used to sensitize chemotherapy to breast cancer with MDR by reducing the efflux of drugs. However, representative P-gp inhibitors usually have severe side effects and the effect of their release behavior on chemotherapy are neglected in current studies. We constructed a nano-in-thermogel delivery system with the sequential release of ginsenoside Rh2 (GRh2) and a chemotherapeutic drug in the tumor microenvironment as a drug compounding "reservoir" to combat MDR in breast cancer. Briefly, paclitaxel (PTX) and GRh2 were encapsulated in solid lipid nanoparticles (SLNs) and dispersed in a poloxamer-based thermogel (SLNs-Gel). GRh2 was used as an innovative and safe P-gp inhibitor to lower P-gp expression and cellular adenosine triphosphate context, thereby sensitizing PTX-resistant breast cancer cells (MCF-7/PTX) to PTX. Pharmacodynamic and in vivo safety studies confirmed that intratumoral injection of SLNs-Gel significantly suppressed the proliferation of PTX-resistant breast cancer and alleviated the PTX-induced hematotoxicity. The GRh2-irrigated nano-in-thermogel delivery system shows great potential in combating multidrug-resistant cancer.