Bovine serum albumin (BSA) decorated lipidic core nanoparticles were constructed for the delivery of quinacrine (Quin) to enhance docetaxel (Dtx) dose-dependent behavior against A-549 lung cancer cells through the inhibition of the Nrf2 signal pathway and arresting the Sub-G1 cell cycle mechanism. Chitosan was chosen as a suitable stabilizer in addressing the proton sponge effect with BSA providing the favorable protein corona formation along with low toxicity. The optimized formulation was characterized in terms of particle size, zeta potential, morphology, polydispersity index and encapsulation efficiency (EE). The mechanism of cytotoxicity, apoptosis and cell cycle arrest along with the determination of the combined efficacy of Quin with Dtx were investigated by MTT assay, flow cytometric assay, CompuSyn and HSA synergy score analysis. Real-time PCR and Western blot analysis were performed to quantify Nrf2-dependent genes and protein levels, respectively. The results demonstrated an average particle size of 112 ± 16.2 nm, a positive surface charge of 15 ± 0.1 mV along with an EE of 65.4 ± 2.6%. Quin NPs reduced the proliferation of lung cancer cells from 68 ± 6.1% to 49 ± 4.5% (p < 0.05) along with a two-fold surge in the percentage of apoptosis (p < 0.05). The incubation of A549 lung cancer cells with Quin NPs caused a significant decrease in Nrf2, NQO1 and MRP1 associated with an increase in BAD mRNA levels compared to the other groups (p < 0.05). Combinational treatment of both Quin + Dtx, as well as Quin NPs + Dtx, induced a remarkable G 2M arrest and sub-G 1 apoptosis. The results, therefore, indicate that Quin-loaded nanoparticles have the ability to enhance the anti-proliferation efficacy of Dtx against A549 lung cancer by inhibiting Nrf2, increasing synergistic interaction with lower doses of Dtx and arresting cell cycle in the Sub-G 1 thus leading to the induction of apoptosis.