This research was performed to synthesize the Citrus aurantium L. bloom essential oil nanoemulsion (CABE‐NE) and investigate its cytotoxic and apoptotic impacts on human lung (A549 cells), and further, the effects of CABE‐NE on mice health parameters was determined. The obtained results demonstrated that C. aurantium bloom contained 1.2 ± 0.16% of essential oil with linalyl acetate, limonene, and α‐terpineol as major compounds. The CABE‐NE possessed particle size of 76.9 ± 6.11 nm, PDI of 0.19, and zeta potential of −43.5 mV. The CABE‐NE indicated the cytotoxicity against A549 cells with the IC50 value of 152 µg/ml. The CABE‐NE induced the overexpression of Cas‐3 and triggered the apoptotic cells death. The mice gavaged daily with CABE‐NE at the concentrations of 10 and 20 mg/kg body weight for 30 days did not show any remarkable histopathological alteration in the liver and kidney while exhibited enhancement in the jejunum morpho‐structural architecture and hepatic antioxidant redox potential. Practical applications According to the results, the produced CABE‐NE drug delivery system could be considered as a promising alternative to prevent lung cancer progression and it provides a new way to enhance the therapeutic value of the plant phytochemicals.