Cancer metastasis after traditional surgery introduces a high barrier to therapy efficacy. Photodynamic therapy (PDT) for cancer is based on a photochemical process of photosensitizers that concentrate in tumors and release oxidant species under light excitation to destroy cells. Compared with traditional surgery, PDT provides minimal invasion and targeted therapy. In this in vivo study, we monitor the real-time and long-term dynamics of circulating tumor cells (CTCs) after a single round of PDT and after surgical resection in a breast cancer animal model. The CTC level is low after PDT treatment, and the recurrence of the primary tumor is postponed in the PDT group compared with the resection group. We find that metastasis is correlated with the CTC level, and the PDT-treated mice show no metastasis in the lung or liver. Our results suggest PDT can effectively reduce metastasis by minimizing CTCs after treatment and is a great technology for breast cancer therapy.