This study aimed to screen the active components of Thymus quinquecostatus with antidepressant effects and to explore the underlying mechanisms based on hippocampal neuroplasticity. A chronic restraint stress (CRS) mouse model of depression was established. The intervention effects of five active components—thyme volatile oil, thymol, carvacrol, p-cymene, and β-caryophyllene (BCP)—were systematically evaluated using behavioral, endocrine, histomorphological, and molecular approaches (50 mg/kg, intraperitoneal injection, once daily for 14 days). All active components significantly reduced serum corticosterone levels (decreased by 27.1%–64.7%, P < 0.001) and increased the sucrose preference rate (increased by 39.5%–55%, P < 0.05). Thymol, carvacrol, and p-cymene significantly shortened immobility time in the tail suspension test (decreased by 8.4%–20.9%), whereas thymol, BCP, and volatile oil effectively reduced feeding latency in the novelty-suppressed feeding test (decreased by 63.4%–67.8%). p-Cymene, BCP, and volatile oil significantly increased the number of BrdU⁺ proliferating cells and DCX+ immature neurons in the hippocampal dentate gyrus (P < 0.05–0.001). All five components increased the number of microglial terminal endpoints by 41%–70%, indicating a shift toward a resting/anti-inflammatory phenotype, and some components also restored astrocyte morphology and density (P < 0.05). All five components significantly activated AKT (p-AKT/AKT increases of more than 91%), whereas only volatile oil, carvacrol, and p-cymene significantly activated CREB (p-CREB/CREB increases of 34%–50%); suggesting that AKT/CREB signaling participates in the regulation of neuronal survival and plasticity. The active components of thyme ameliorated depression-like behaviors in mice through multi-target synergistic effects, including inhibiting HPA axis overactivation, promoting neurogenesis, inducing glial anti-inflammatory phenotype transformation, and activating AKT/CREB survival signaling. Among them, p-cymene, BCP, carvacrol, and volatile oil displayed promising therapeutic potential, providing an experimental basis for the development of natural multi-target antidepressants based on neural stem cell–glial cell network regulation.