Carboplatin is extensively used in the first-line treatment of ovarian cancer. Although the majority of patients respond to platinum-based therapy, platinum resistance limits the efficiency of treatment in the clinical setting. During treatment, DNA methylation leads to epigenetic silencing of tumor suppressor genes and cancer cells lose their sensitivity to platinum-based compounds. The therapeutic utilization of decitabine, which is an epigenetic demethylating agent, in combination with carboplatin is considered as a novel method for overcoming drug resistance in ovarian cancer. In this study, we developed a pH-responsive lipid-coated nanoparticular system that was co-loaded with carboplatin and decitabine to modulate the platinum resistance. The nanoparticles exhibited a core-shell structure of 350 ± 12 nm particle size, −57 ± 2 mV surface charge. The cytotoxicity studies demonstrated that cytotoxic effect of carboplatin was achieved at significantly lower doses in platinum-sensitive and platinum-resistant ovarian cancer cells. In addition, confirmation of apoptosis by caspase and PARP cleavage in both cells strongly supported the efficacy of the nanoparticular system. Notably, dual drug-loaded nanoparticles led to MLH1 re-expression in resistant ovarian cancer cells, which may be attributed to improved drug sensitivity in cells. Overall, the developed nanoformulation has great potential for the treatment of platinum-sensitive as well as platinum-resistant ovarian cancer.