Cerium dioxide nanoparticles have many applications including use as a diesel fuel additive. Concerns over the increased use of engineered nanoparticles and the potential risks to the public have led many studies to investigate the health impacts after nanomaterial exposure. For CeO2 nanoparticles, some studies report oxidative stress leading to a loss of cell viability, where others report the opposite, observing protective effects against oxidative stress induced injury. Due to a lack of consensus over the precise physiological effects surrounding CeO2 exposure, we set out to investigate how these particles influence oxidative stress induced injury. To model the lung as a primary exposure location we used alveolar type II epithelial cells (A549) incubated with CeO2 nanoparticles, prior to an oxidative stress event using either H2O2 or Menadione. Nanoparticle exposure protected against oxidant-induced injury but this was not paralleled by a reduction in the oxidative stress markers such as protein carbonylation or expression of EGR1 and NQO1. Using gene expression profiling TGF-β signalling was identified as a candidate mechanism through which the CeO2 nanoparticles were having their protective effects. Using recombinant transforming growth factor beta 1 (TGF-β1) we demonstrate protective effects on oxidant-induced injury paralleled by alterations in TGF-β pathway related gene expression similar to those observed with CeO2 nanoparticle addition. These results represent an important addition to our understanding of the biological effects of CeO2 nanoparticles and identify TGF-β signalling as a potential mechanistic regulator for their cyto-protective ability.