Astrocytes are greatly impacted by oxidative stress, which can also be related to neurodegenerative diseases. Therefore, preventing the production of reactive oxygen species (ROS) is crucial for maintaining healthy cells. Large conductance Ca2+-activated big potassium (BK) channel openers are effective in eliminating the effects of oxidative stress. The present study aims to determine if NS11021, a BK channel opener, protects the astrocytes from harmful effects of hydrogen peroxide (H2O2), which is an oxidative stress inducer. For this purpose, primary astrocyte cultures were incubated with H2O2, NS11021, and Iberiotoxin both separately and together. H2O2 decreased cell viability by approximately 50% and increased the number of ROS-positive astrocytes. However, NS11021, but not Iberiotoxin, reversed the deleterious effects of H2O2 on cell viability and decreased ROS production. Moreover, dysregulations in Cyclin D1/CDK6/p21 gene expressions under conditions of oxidative stress were regulated again by the opener. To the best of our knowledge, this study has been the first to reveal that NS11021 reversed the deleterious effects of H2O2 on cell viability by regulating ROS production in astrocytes. Its effect may also be related to the regulation of cell cycle at the transcriptional level. NS11021 may also be used as an agent for the treatment of oxidative-stress related dysfunction of astrocytes.