Magnolia bark and ginger rhizome is a drug pair in many prescriptions for treatment of mental disorders in traditional Chinese medicine (TCM). However, compatibility and synergism mechanism of two herbs on antidepressant actions have not been reported. The aim of this study was to approach the rationale of the drug pair in TCM. We evaluated antidepressant-like effects of mixture of honokiol and magnolol (HMM), polysaccharides (PMB) from magnolia bark, essential oil (OGR) and polysaccharides (PGR) from ginger rhizome alone, and the possibility of synergistic interactions in their combinations in the mouse forced swimming test (FST) and tail suspension test (TST). Serotonin (5-HT) and noradrenaline (NE) levels in prefrontal cortex, hippocampus and striatum were also examined. 30 mg/kg HMM decreased immobility in the FST and TST in mice after one- and two-week treatment. OGR (19.5 or 39 mg/kg) alone was ineffective. The combination of an ineffective dose of 39 mg/kg OGR with 15 mg/kg HMM was the most effective and produced a synergistic action on behaviors after two-week treatment. Significant increase in 5-HT and synergistic increase in NE in prefrontal cortex were observed after co-administration of HMM with OGR. These results demonstrated that HMM was the principal component of this drug pair, whereas OGR served as adjuvant fraction. Compatibility of HMM with OGR was suggested to exert synergistic antidepressant actions by attenuating abnormalities in serotonergic and noradrenergic system functions. Therefore, we confirmed the rationality of drug pair in clinical application and provided a novel perspective in drug pair of TCM researches.