Depression is associated with a dysfunctional serotonin (5-hydroxytryptamine; 5-HT) system. More recently, several lines of evidence suggest that an important factor in the development of depression may be a deficit in the function and expression of 5-HT1A receptors. The present study assessed if Nelumbinis Semen (N.s.) had an anti-depression effect through reversing a decrease in 5-HT1A receptor binding in rats with depression-like symptoms induced by chronic mild stress. Using a 5-HT1A receptor binding assay, with a specific 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin), the mechanism of the anti-depression effect of N.s. on rats was investigated, and the effects compared with two well-known antidepressants, Hyperium Perforatum (St. Johns Wort) and fluoxetine (Prozac). Animals were divided into five groups: the normal (N) group without chronic mild stress (CMS), the control (C) group under CMS for 8 weeks, the Nelumbinis Semen (N.s.) treatment group under CMS for 8 weeks, the Hyperium Perforatum (H.p.) treatment group under CMS for 8 weeks and finally, the fluoxetine (F) treatment group under CMS for 8 weeks. Each treatment was administered to rats during the last 4 weeks of the 8-week CMS. A sucrose intake test was performed to test the anti-depression effect of N.s. The N.s. treatment significantly reversed the decreased sucrose intake under CMS (P < 0.05 compared to control group under CMS). In the CA2 and CA3 regions of the hippocampus, both N.s. and H.p. reversed the CMS-induced decrease in 5-HT1A receptor binding. In the I to II regions of the frontal cortex, N.s. and H.p. also reversed the CMS-induced decrease in 5-HT1A receptor binding, and even showed a significant increase in 5-HT1A receptor binding compared to the F treatment group (N.s. vs. P, p < 0.05, H.p. vs. P, p < 0.05). However, in the hypothalamus, all treatments reversed the CMS-induced decrease in 5-HT1A receptor binding. This reversal effect of N.s. on the decrease in 5-HT1A receptor binding in the frontal cortex, hippocampus and hypothalamus of rat brains was very similar to that of H.p, but different from that of F. It is concluded that N.s. presents an anti-depression effect through enhancing 5-HT1A receptor binding.