Oxidative stress can induce neurotoxic insults by increasing intracellular calcium (Ca2+), which has been implicated in various neurodegenerative diseases in aging. Previously, we showed that hydrogen peroxide induced calcium dysregulation in PC12 cells, as evidenced by (i) an increase in calcium baselines, (ii) a decrease in depolarization-induced calcium influx, and (iii) a failure to recover the Ca2+ levels. In the present experiments, we investigated whether a dietary flavonoid, quercetin, can antagonize the effects of hydrogen peroxide in the same cell model. We also investigated the possible structure-activity relationships of quercetin by comparing the results with four other flavonoids, each having a slightly different structure from quercetin. Our results indicated that two structural components, including (i) 3', 4'-hydroxyl (OH) groups in the B ring and (ii) a 2,3-double bond in conjugation with a 4-oxo group in the C ring, along with the polyphenolic structures were crucial for the protection. These structural components are found in quercetin, and this compound was also the most efficacious in reducing both the H2O2-induced Ca2+ dysregulation in cells and oxidative stress assessed via the dichlorofluorescein assay. Collectively, these data indicated that the particular polyphenolic structural components of quercetin provided its strong antioxidant property of protecting cells against H2O2-induced oxidative stress and calcium dysregulation.