p53 is a crucial transcription factor with tumor suppressive properties that elicits its function through specific target genes. It constitutes a pivotal system that integrates information received by many signaling pathways and subsequently orchestrates cell fate decisions, namely, growth-arrest, senescence, or apoptosis. Reactive oxygen species (ROS) production in cells can play a key role in signal transduction, being able to trigger different processes as cell death or cell proliferation. Sustained oxidative stress can induce genomic instability and collaborates with cancer development, whereas acute enhancement of high ROS levels leads to toxic oxidative cell damage and cell death. Here, it has been considered p53 broad potential contribution through its ability to regulate selected key cancer signaling pathways, where ROS participate as inductors or effectors of the final biological outcome. Further, we have discussed how p53 could play a role in preventing potentially harmful oxidative state and cell proliferation by pro-oncogenic pathways such as PI3K/AKT/mTOR and WNT/β-catenin or under hypoxia state. In addition, we have considered potential mechanisms by which p53 could collaborate with signal transduction pathways such as transforming growth factor-β (TGF-β) and stress-activated protein kinases (SAPK) that produce ROS, to stop or eliminate uncontrolled proliferating cells.