Abstract Background TMS is an effective anti-depression method commonly used in clinical practice, but it also faces the problems of low spatial resolution, treatment parameters to be optimized and limitation in mechanism research. Objective To develop a precise magnetic stimulation anti-depression method for the scientific research of magnetic stimulation, especially the mechanism research in animal experiments. Methods The cytotoxicity test was conducted in advance to ensure the security of intervention from SPIO nanoparticles and RMF. In animal experiments, 300nl SPIO solution was injected into the right hippocampus of the CUMS model mice, and then treated experimental group mice with rotating magnetic field for five days. The Sucrose Preference Test (SPT), the Forced Swim Test (FST) and BDNF expression levels were used to evaluate the antidepressant effect of this method. Results No significant decrease of cell viability was observed when the iron concentration is between 52.2µg/ml and 208.8µg/ml. And the application of RMF with a certain frequency was considered to be safe in the cytotoxicity test. When treated with SPIO+RMF, the sucrose preference of SPIO+RMF group mice increased markedly (n=9, p<0.01 vs. CUMS), the FST immobile time reduced (n=8, P<0.05 vs. CUMS) and the BDNF level in the hippocampus was significantly up-regulated (n=5, P<0.01 vs. CUMS). However, merely SPIO intervention failed to be effective. Conclusions when intervened with external rotating magnetic field, the SPIO nanoparticles injected into the right hippocampus could produce rapid antidepressent effects in mice.