Purpose. The current investigation is on the explicit development and evaluation of nanostructured lipidic carriers (NLCs) through the oral route to overcome the inherent lacuna of chemotherapeutic drug, in which Ribociclib (RBO) was used for breast cancer to diminish the bioavailability issue. Method. The RBO‐NLCs were prepared using the solvent evaporation method and optimized method by the Box–Behnken design (BBD). Various assessment parameters characterized the optimized formulation and their in vivo study. Results. The prepared NLCs exhibited mean particle size of 114.23 ± 2.75 nm, mean polydispersity index of 0.649 ± 0.043, and high entrapment efficiency of 87.7 ± 1.79%. The structural analysis by TEM revealed the spherical size of NLCs and uniform drug distribution. An in vitro drug release study was established through the 0.1 N HCl pH 1.2, acetate buffer pH 4.5, and phosphate buffer pH 6.8 with % cumulative drug release of 86.71 ± 8.14, 85.82 ± 4.58, and 70.98 ± 5.69%, was found respectively, compared with the RBO suspension (RBO‐SUS). In vitro intestinal gut permeation studies unveiled a 1.95‐fold gain in gut permeation by RBO‐NLCs compared with RBO‐SUS. In vitro lipolysis suggests the drug availability at the absorption site. In vitro haemolysis study suggests the compatibility of NLCs to red blood cells compared to the suspension of the pure drug. The confocal study revealed the depth of penetration of the drug into the intestine by RBO‐NLCs which was enhanced compared to RBO‐SUS. A cell line study was done in MCF‐7 and significantly reduced the IC₅₀ value compared to the pure drug. The in vivo parameters suggested the enhanced bioavailability by 3.54 times of RBO‐NLCs as compared to RBO‐SUS. Conclusion. The in vitro, ex vivo, and in vivo results showed a prominent potential for bioavailability enhancement of RBO and effective breast cancer therapy.