To observe the effect of repetitive transcranial magnetic stimulation (rTMS) combined with music therapy on post-stroke depression (PSD), and to investigate its possible mechanism. Methods: A total of 69 patients with PSD were divided into the control group (23 cases), TMS group (21 cases), and combined treatment group (25 cases); the groups were treated with conventional therapy, conventional therapy + rTMS, or conventional therapy + rTMS + music therapy, respectively, for 4 weeks. The Hamilton Depression Scale (HAMD) was used to evaluate depression and the modified Barthel index (mBI) to assess activities of daily living in patients at hospital admission and again at 4 weeks after treatment. The serum level of 5-hydroxytryptamine (5-HT) in each group was measured at the same time points. Results: The HAMD score, mBI score, and 5-HT level were not significantly different between the 3 groups before treatment (P>0.05). Compared to before treatment, the HAMD score of each group 4 weeks after treatment showed improvement, and the combined treatment group showed greater effectiveness than the other 2 groups (P<0.05). The mBI score and 5-HT level in each group was higher after treatment compared to the same group before treatment, and the combined group showed a greater increase than those of the other 2 groups (P<0.05). Conclusion: Repetitive TMS combined with music therapy is effective in the treatment of PSD, significantly reducing depression scores and increasing quality of life; the mechanism may be related to the increase in serum 5-HT levels.