Multidrug resistance (MDR) remains the primary issue leading to the failure of chemotherapy. In this study, a d-α-tocopherol polyethylene 1000 glycol succinate (TPGS) and chondroitin sulfate (CS) dual-modified lipid-albumin nanosystem was constructed for targeted delivery of paclitaxel (PTX) in treating MDR cancer. The obtained nanosystem (TLA/PTX@CS) had an average size of around 176 nm and a negative zeta potential of around −18 mV. TPGS was confirmed to improve the intracellular accumulation of PTX and facilitate the mitochondrial-targeting of lipid-albumin nanosystem. Functionalized with the outer CS shell, TLA/PTX@CS entered MDR breast cancer (MCF-7/MDR) cells via CD44 receptor-mediated endocytosis. CS shell was degraded by concentrated hyaluronidase in the lysosomes, thereby releasing PTX into cytoplasm and inhibiting cell proliferation. In vivo studies revealed that TLA/PTX@CS possessed prolonged blood circulation, resulting in elevated tumor accumulation, excellent antitumor efficacy with a tumor inhibition ratio of 75.3%, and significant survival benefit in MCF-7/MDR tumor-bearing mice. Hence, this TPGS and CS dual-modified lipid-albumin nanosystem provides a promising strategy for targeted delivery of chemotherapeutic drug and reversal of MDR in cancer treatment.