Bosutinib (BOS), a BCS class IV drug suffers from poor aqueous solubility and bioavailability along with significant food effect. Lipid nanocarriers (LNC) have the potential to circumvent bioavailability related issues associated with hydrophobic moieties. In this endeavor, we explore the potential of novel lipid nanocarriers to circumvent the bioavailability pitfalls, while minimizing food effect and pharmacokinetic variability. Quality by design and multi-variate analysis was adopted for the optimization of various process parameters during nanoparticle fabrication. The optimized particle size, polydispersity index (PDI) and zeta potential were found to be 131.7 nm, 0.105 and −9.29 mV respectively. Ex vivo studies revealed improved intestinal permeation of LNC. Enhancements in cytotoxicity, ROS generation and apoptosis were observed against MCF-7 cells that could be attributed to elevated intracellular drug accumulation using LNC. Pharmacokinetic studies revealed a 2.6-fold increase in the bioavailability of BOS during fasted state and a 1.36-fold increase during fed state when BOS was administered via LNC, indicating superior oral bioavailability. Cmax fast/fed was found to be 0.94 while, AUC fast/fed was 0.9258 which was close to 1, indicating attenuation of the food effect by BOS LNC. Therefore, LNCs can serve as promising delivery carriers for attenuation of food effect during breast cancer therapy.