Objective Different tandospirone citrate compositions（TCCs）were screened to assess their effectiveness in improving depressive behaviors in mice and to explore the neuroprotective effects of the most effective combinations. Methods Animal behavioral experiments and in vitro cellular experiments were used. In animal experiments，the effects of five TCCs on depression-like behaviors in mice were evaluated by the forced swim test（FST）and tail suspension test（TST）. In vitro experiments were conducted to investigate the effects of TCC-4，which exhibited the best performance，on inhibiting hydrogen peroxide（H2O2）-induced damage in PC-12 cells and lipopolysaccharide（LPS）-induced neuroinflammation in BV-2 cells. Results In FST and TST experiments，TCCs significantly reduced the resting time of mice（P < 0.05），showing their antidepressant-like effects. In H2O2-induced PC-12 cells，the bestperforming TCC-4 was found to effectively inhibit cell death，reactive oxygen species（ROS）production，and mitochondrial membrane potential（MMP）reduction（P < 0.001）. Additionally，TCC-4 could attenuate LPS-induced BV-2 cell activation and phagocytosis （P < 0.001）. Conclusion TCCs，especially TCC-4，showed favorable antidepressant effects. The mechanism of action might be related to the inhibition of oxidative damage in neurons and the regulation of microglia activation. These findings provided support for the potential of TCC-4 as a novel antidepressant drug and laid the foundation for further studies on its clinical application.