This study aimed to formulate the hesperetin nanostructured lipid carriers (NLCs) containing oro-mucosal gel for its activity assessment on the KB cell line. NLCs were prepared with glyceryl monostearate, oleic acid, and lecithin using a modified constant-temperature emulsification technique. The particle size analysis, in vitro drug release studies, etc., of prepared NLCs were evaluated. The formulated gels were analyzed with respect to spreadability, extrudability, swelling index, texture analysis, etc. The particle size, polydispersity index, zeta potential, and drug entrapment of nanocarriers were recorded to be 221.733 ± 61.536 nm, 0.381 ± 0.091, - 51.433 ± 4.143 mV, and 89.29%, respectively. The optimized NLCs in 24 h released 87.14 ± 6.62% of the drug. The round shape of NLCs was noticed with scanning electron microscopy. The pH, spreadability, extrudability, swelling index, content uniformity, and drug release studies of hesperetin NLCs-containing gel (HNG) were found to be 6.81 ± 0.04, 2.49 ± 0.04 cm.mg/s, 539.04 ± 32.88 g/cm2, 4.27 ± 0.47, 107.98 ± 1.93%, and 90.17 ± 6.67% (in 48 h), respectively. The developed formulations showed promising in vitro anticancer and antioxidant activities. HNP results authorize that the formulation may be beneficial for the treatment of oral cancer.