Objective: This study aims to investigate the effect of gardenia/acanthopanax-medicated serum on pheochromocytoma (PC12) cell apoptosis and calcium ion concentration, and explore the antidepression mechanism of gardenia/acanthopanax. Materials and Methods: In this study, PC12 cells were treated with high concentrations of corticosterone to simulate the effect of high level glucocorticoids in neurons in patients with depression. Next, the apoptosis rate of cells, apoptosis-related proteins, and relative intracellular calcium concentration were detected using flow cytometry. Results: Compared with the blank group, the apoptosis rates, pro-apoptotic proteins, and calcium ion concentrations were significantly increased, and the anti-apoptotic proteins decreased in the control groups, and the results were reversed by different drug-medicated serum. Compared with the control groups, the differences in gardenia and fluoxetine groups were statistically significant (P < 0.01) and were more significant than acanthopanax group (P < 0.05); but the differences between the gardenia and fluoxetine groups were not statistically significant (P > 0.05). Conclusion: The results of this study suggest that gardenia/acanthopanax-medicated serum can obviously improve the survival rate of neurons under high concentrations of glucocorticoids, downregulate the apoptosis-related proteins, and reduce the intracellular calcium concentration, and gardenia had better effects than acanthopanax.