Accumulation of reactive oxygen species (ROS) beyond the cellular antioxidant capacity can disrupt redox homeostasis and promote apoptotic cell death, providing a potential strategy for targeting cancer cells. This study investigated the anticancer effects of Schisandrin A (Sch A), a bioactive lignan derived from Schisandra chinensis, and the underlying role of ROS in esophageal squamous cell carcinoma (ESCC). Treatment with Sch A effectively reduced cell viability and clonogenic growth in KYSE30 and KYSE510 ESCC cells, whereas relatively limited cytotoxicity was observed in normal HEKa cells. Sch A markedly increased intracellular ROS levels and was accompanied by mitochondrial dysfunction and activation of apoptosis-associated signaling. In parallel, Sch A altered the expression of cell cycle regulatory proteins and promoted G0/G1 phase arrest, further contributing to the suppression of ESCC cell growth. Importantly, pharmacological scavenging of ROS with N-acetyl-L-cysteine (NAC) attenuated Sch A-induced cytotoxicity, indicating that ROS generation plays an important role in its anticancer activity. Together, these findings indicate that Sch A disrupts redox homeostasis in ESCC cells, leading to mitochondrial dysfunction, apoptotic cell death, and impaired cell cycle progression. These results provide further evidence for the potential of Sch A as a natural compound for targeting ESCC through ROS-associated mechanisms.