The controversial outcomes in patients with metastatic colorectal cancer (mCRC) highlight the need for developing effective systemic neoadjuvant treatment strategies to improve clinical results. The optimal treatment cycles in patients with mCRC for metastasectomy remain undefined. This retrospective study compared the efficacy, safety, and survival of cycles of neoadjuvant chemotherapy/targeted therapy for such patients. Sixty-four patients with mCRC who received neoadjuvant chemotherapy/targeted therapy following metastasectomy were enrolled between January 2018 and April 2022. Twenty-eight patients received 6 cycles of chemotherapy/targeted therapy, whereas 36 patients received ≥7 cycles (median, 13; range, 7–20). Clinical outcomes, including response, progression-free survival (PFS), overall survival (OS), and adverse events, were compared between these two groups. Of the 64 patients, 47 (73.4%) were included in the response group, and 17 (26.6%) were included in the nonresponse group. The analysis revealed chemotherapy/targeted therapy cycle and pretreatment serum carcinoembryonic antigen (CEA) level as independent predictors of the response as well as overall survival and chemotherapy/targeted therapy cycle as an independent predictor of progression (allp< 0.05). Furthermore, our results revealed shorter operation time, lower estimated operative blood loss, higher response rate, lower progression rate, and higher survival rate in ≥7 cycles of chemotherapy/targeted therapy group (allp< 0.05), but no statistical differences in adverse events were observed between the two groups (allp> 0.05). The median OS and PFS were 48 months (95% CI, 40.855–55.145) and 28 months (95% CI, 18.952–37.48) in the ≥7-cycle group and 24 months (95% CI, 22.038–25.962) and 13 months (95% CI, 11.674–14.326) in the 6-cycle group, respectively (bothp< 0.001). The oncological outcomes in the ≥7-cycle group were significantly better than those in the 6-cycle group, without significant increases in adverse events. However, prospective randomized trials are mandatory to confirm the potential advantages of cycle numbers of neoadjuvant chemotherapy/targeted therapy.