Reactive oxygen species (ROS) generation is a usual phenomenon in a plant both under a normal and stressed condition. However, under unfavorable or adverse conditions, ROS production exceeds the capacity of the antioxidant defense system. Both non-enzymatic and enzymatic components of the antioxidant defense system either detoxify or scavenge ROS and mitigate their deleterious effects. The Ascorbate-Glutathione (AsA-GSH) pathway, also known as Asada-Halliwell pathway comprises of AsA, GSH, and four enzymes viz. ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase, play a vital role in detoxifying ROS. Apart from ROS detoxification, they also interact with other defense systems in plants and protect the plants from various abiotic stress-induced damages. Several plant studies revealed that the upregulation or overexpression of AsA-GSH pathway enzymes and the enhancement of the AsA and GSH levels conferred plants better tolerance to abiotic stresses by reducing the ROS. In this review, we summarize the recent progress of the research on AsA-GSH pathway in terms of oxidative stress tolerance in plants. We also focus on the defense mechanisms as well as molecular interactions.