Fusobacterium nucleatum is an obligate anaerobic bacterium found in the indigenous human microbiota but also recovered from several anaerobic infections. Considering the biological and medical relevance of F. nucleatum, the characterization of its response to oxidative stress is needed in order to understand how this anaerobic bacterium survives during an invasive process of oxygenated tissues. Influence of oxidative stress by atmospheric oxygen exposure on cellular morphology and pathogenicity of F. nucleatum were investigated. The wild-type F. nucleatum ATCC 25586 (wt-strain) was exposed to oxidative stress to select an adapted strain (aero-strain). Conventional NIH Swiss mice were split in two experimental groups which were challenged intraperitoneally with wt-strain and aero-strain, respectively, and a control group, unchallenged. Histopathological and hyperemia analysis were performed by day 30 after infection. Gram stain of aero-strain showed drastic changes in cellular morphology when compared to wt-strain. A significant increase of liver weight/body weight ratio (P < 0.05) as well as a tendency (P = 0.16) to higher spleen weight/body weight ratio were observed for the mice challenged with aero-strain when compared to the two other animal groups. Additionally, these animals also showed hyperemia in the spleen and liver as well as an increased number of inflammatory cells and steatosis in the liver. The results showed that, in addition to extensive changes in cell morphology, the adaptation to oxidative stress might also influence the pathogenicity of F. nucleatum. These findings have clinical implications since in the host tissues this indigenous putative pathogen is exposed to more or less oxygenated environments found on the different anatomic sites invaded by the bacterium.