The T-2 toxin is one of the most toxic mycotoxins, to which the population is exposed through the diet. T-2 toxins are especially found in cereals and cereal-based products. To deepen our understanding of the mechanisms of T-2 toxin action, the morphological changes, oxidative stress, and inflammatory response of this mycotoxin have been evaluated in HepG2 cells. The mRNA and protein expression levels of inflammatory cytokines such as IL-1β, IL-6, and TNF-α and proteins such as Nrf2 and HO-1 were analyzed after T-2 exposure (7.5, 15, and 30 nM) by qPCR and Western blot assays. Firstly, changes in the morphology of HepG2 cells after T-2 exposure from circular to elongated shape were observed in a concentration-dependent manner by indirect immunofluorescence. These alterations may reflect early signs of cell stress. The results revealed an upregulation of the mRNA of IL-1β, IL-6, and TNF-α after T-2 exposure, with the highest increase in TNF-α after 30 nM T-2, suggesting a proinflammatory effect. Regarding the oxidative response, HO-1 at the lowest T-2 concentration was upregulated. However, the Nrf2 at all T-2 concentrations tested was downregulated. These findings were corroborated by Western blot analysis. These results confirm that T-2 hepatotoxicity produces an increase in key inflammatory cytokines, modulates the Nrf2/HO-1 pathway, and produces morphological changes in HepG2 cells. The next step would be to test whether a co-exposure of natural antioxidants with T-2 exerts a cytoprotective effect.