Neurodegenerative diseases (NDDs) are a range of neurological disorders featured by neuronal degeneration and apoptosis. Cellular Calcium (Ca2+) and reactive oxygen species (ROS) dyshomeostasis are the earliest and important events in the development of NDDs and may yield promising therapeutic targets for NDDs. Paeoniflorin, a water-soluble monoterpene glucoside, is the major bioactive monomer extracted from the root of Paeonia lactiflora pall. Increasing evidence has suggested that this natural compound might be used to treat various NDDs, and its potential molecular mechanisms are related to the modulation of Ca2+/ROS homeostasis in cells. In addition, paeoniflorin accounts for more than 40% of the total glucosides of herbaceous peonies with abundant herbaceous sources. Furthermore, it has also been validated as a safe extraction in clinical pharmacological research with a wide therapeutic window. Hence, it is rational to anticipate paeoniflorin being a promising candidate for the treatment of NDDs via regulating Ca2+/ROS dyshomeostasis.