The blood-brain barrier (BBB) plays critical roles in maintaining the stability of the brain's internal milieu, providing nutrients for the brain, and preventing toxic materials from the blood from entering the brain. The cellular structure of the BBB is mainly composed of brain microvascular endothelial cells (BMVECs), which are surrounded by astrocytic endfeet that are connected by tight junction proteins, pericytes and astrocytes. Recently, several studies have shown that aberrant increase in intracellular calcium levels in BMVECs lead to cellular metabolic disturbances and subsequent impairment of BBB integrity. Although multiple stresses can lead to intracellular calcium accumulation, inherent protective mechanisms in affected cells are subsequently activated to maintain calcium homeostasis. However, once the increase in intracellular calcium goes beyond a certain threshold, disturbances in cellular structures, protein expression, and the BBB permeability are inevitable. Here, we review recent research on the different factors regulating intracellular calcium concentrations and the mechanisms related to how calcium signaling cascades protect the BMVECs from outside injury. We also consider the potential of calcium signaling regulators as therapeutic targets for modulating intracellular calcium homeostasis and ameliorating BBB disruption in patients with calcium-related pathologies.