Heavy metals and Brominated diphenyl ether flame-retardants (BDEs) often coexist in the environment and are capable of inducing injury, cytotoxicity or genotoxicity in human epithelial cells of the lung. We studied the effects of single Cadmium chloride (CdCl2) or CdCl2/BDE (47 or 209) mixtures in airway epithelial cells, using A549 cell line cultured at submerged conditions and air–liquid interface (ALI) (an in vitro model described as physiologically relevant in vivo-like). We evaluated cell viability, oxidative stress, apoptosis, DNA damage/repair (Comet assay, γH2AX phosphorylation ser139), mitochondrial redox balance (NOX-4, Nrf2 and TFAM) and cell barrier integrity (TEER, ZO-1, Claudin-1, E-cadherin-1) in A549 cells exposed to CdCl2 (1 nM to 10 µM), or to CdCl2 (100 nM)/BDEs (47 or 209) (100 nM). CdCl2 (10 μM) reduced cell viability and increased apoptosis. CdCl2 (100 nM) significantly affected DNA-damage/repair (Olive Tail length production), γH2AX phosphorylation and oxidative stress (ROS/JC-1 production) in submerged cell cultures. CdCl2 (100 nM) decreased viability, TEER, ZO-1, Claudin-1 and E-cadherin-1 mRNA expression, and Nrf2 and TFAM while increased NOX-4, in ALI culture of cells. In both cell culture approaches, the cells stimulated with Cadmium/BDEs mixtures did not show a significant increase in the effects observed in the cells treated with CdCl2 alone. CdCl2 inhalation might exert cytotoxicity and genotoxicity, playing a pivotal role in the uncontrolled oxidative stress, damaging DNA and gene expression in airway epithelial cells. No additional or synergistic adverse effects of CdCl2/BDEs mixture were observed in comparison to CdCl2 alone in lung epithelium.