P-glycoprotein (P-gp) induced multidrug resistance (MDR) is the main reason for the failure of cancer chemotherapy. The combined delivery of chemodrug and P-gp inhibitor is a promising pathway to reverse MDR. However, the intrinsic stimuli in the tumor microenvironment could not realize a complete drug release, which would induce poor cancer therapeutic efficacy. Herein, we conjugated tamoxifen (TAM) with D-α-tocopherol polyethylene glycol1000 succinate (TPGS) based on a reactive oxygen species (ROS)-responsive aryl boronic ester bond to construct a self-amplified ROS-responsive chemodrug–inhibitor (TPGS–TAM) co-delivery system. Due to its amphiphilic property, the TPGS–TAM conjugates could self-assemble into uniform spherical nanoparticles (NPs). After effective endocytosis by cancer cells, the intracellular ROS cleaved the aryl boronic ester bond and initiated the release of TAM and α-tocopherol succinate (α-TOS) from the NPs. Subsequently, the released α-TOS further generated ROS to facilitate the release of TAM. Moreover, α-TOS also consumed adenosine triphosphate (ATP) to impair ATP-dependent P-gp mediated drug efflux to reverse the tumor's drug resistance. As a result, the TPGS–TAM NPs enhanced the antitumor effect with a tumor inhibition rate (TIR) high up to 74.6 ± 6.1% in an MCF-7/ADR tumor model. Based on systematic in vitro and in vivo assessments, this self-amplified ROS-responsive carrier-free conjugate of chemodrug/P-gp inhibitor may shed light on the potential application for the MDR cancer therapy.