BACKGROUND: Lung cancer (LC) is the leading cause of malignancy-related mortalities globally, and the existing treatment interventions are associated with harmful side effects. In the current study, we evaluated the anti-tumor efficiency of nerolidol (NRD) on human non-small cell lung cancer (NSCLC) cells. OBJECTIVES: Nerolidol is a sesquiterpene alcohol extracted from the essential oils of aromatic flora with known anti-cancer activities. MATERIAL AND METHODS: The latent action of NRD on antiproliferative and apoptotic effects in A549 cells is uncertain. Thus, our work is designed to explore the antiproliferative and apoptotic actions of NRD (20 and 25 μM/mL) against A549 cells. The activity of NRD on A549 cell cytotoxicity, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), apoptosis, anti-apoptotic proteins, and MAPK/TAT3/NF-κB and P13K/AKT signaling pathways were assessed using MTT tests, dichlorodihydrofluorescein diacetate (DCFH-DA), dual acridine orange/ethidium bromide (AO/EB), DAPI, Rh-123, reverse transciption polymerase chain reaction (RT-PCR), and western blot analyses. RESULTS: We found that NRD could inhibit NSCLC cell viability through elevated intracellular ROS and MMP loss and elicited apoptosis in a quantity-dependent manner. Similarly, NRD can reduce inflammatory cytokines and anti-apoptotic elements, as well as trigger apoptotic signaling pathways. CONCLUSIONS: Our data established that NRD decreases A549 cell proliferation through ROS-mediated apoptosis, triggering the MAPK/STAT3/NF-κB and P13K/AKT pathways, suggesting that NRD is a possible protective remedy for NSCLC.