The present study investigated antidepressant-like interaction of five herb polysaccharide fractions from Banxia-Houpu decoction, composed of rhizome pinelliae (PRP), magnolia bark (PMB), poria (PPO), ginger rhizome (PGR) and folium perillae (PFP) by a L(16)(2(5)) orthogonal array design with a two-factor interaction in the tail suspension and forced swimming and tests (TST, FST) in mice. Serotonin (5-HT) and dopamine (DA) levels in whole mouse brain were simultaneously examined after the FST exposure. Polysaccharides PMB, PPO, PFP, and interactions of PRP x PGR, PMB x PFP, PPO x PFP reduced immobility in the mouse FST. Furthermore, PMB and PPO were two principal components of polysaccharides elevating brain 5-HT levels. PFP was an adjuvant component elevating brain DA levels. These results demonstrated that ineffective PRP exhibited antidepressant-like effects when combined with another ineffective PGR, and PFP played a role in assisting effects of PMB and PPO. Therefore, PMB x PFP and PPO x PFP interactions on antidepressant-like effects were the cores in compatibility of polysaccharides from Banxia-Houpu decoction by attenuating abnormalities in the serotonergic and dopaminergic system functions in animal models of depression.