In vivo, migrating cells often encounter microenvironments that impose spatial constraints, leading to cell and nuclear deformation. As confinement-induced DNA damage has been linked to the accumulation of reactive oxygen species (ROS), we sought to investigate the impact of oxidative stress on cell behavior within confined spaces. Using microchannel devices that enable control of the degree and duration of cell confinement, we demonstrate that confined migration increases ROS levels in both HT-1080 fibrosarcoma cells and human dermal fibroblasts. Treatment with the antioxidant N-Acetyl-L-cysteine (NAC) counteracts confinement-induced ROS accumulation, suppressing p53 activation and supporting cell survival in both cell lines. This intervention preferentially reduces dorsal perinuclear actin fibers in confined cancer cells. Loss of these fibers is associated with reduced nuclear rupture frequency and increased confined migration. Collectively, this work provides insights into the differential effects of ROS on cancerous and non-cancerous cells and suggests that antioxidants may support tumor progression.