Breast cancer has the highest incidence rates among all cancers, which represent a global health concern. Effective chemotherapy for breast cancer must minimize adverse effects to improve patient outcomes. Palbociclib (PB), a CDK 4/6 inhibitor, restricts cell growth and suppresses DNA replication in the retinoblastoma tumor suppressor gene (RB). Despite its breakthrough status postapproval, PB is associated with severe side effects, including neutropenia, leukopenia, infections, and thrombocytopenia. The current study aims to develop and optimize a PB-loaded lipidic nanocarrier. The development method was solvent evaporation, and formulation optimization was performed using a central composite rotatable design. Characterization of the nanostructured lipid carrier (NLC) showed a particle size of 129.8 ± 7.6 nm with a PDI of 0.2694 ± 0.04 and a zeta potential of -29.8 ± 2.4 mV. Surface morphology was studied using transmission electron microscopy, which confirmed the particles' uniform and spherical shape. In vitro release studies in 0.1 N HCl and pH 6.8 phosphate buffer demonstrated cumulative drug releases of 91.23 ± 2.1% and 72.9 ± 2.0%, respectively. Intestinal permeation studies demonstrated a 3.76-fold increase in gut permeation with PB-NLC compared to that with PB-Sus. The lipolysis study indicated an enhanced drug availability at the site of absorption. Confocal studies revealed improved drug penetration depth in the intestine with PB-NLC compared to that with PB-Sus. In vivo pharmacokinetic studies demonstrated that incorporating PB into a lipidic nanocarrier (PB-NLC) significantly enhanced its bioavailability by approximately 5.9-fold (