Abstract: Objective To evaluate the efficacy and safety of a sequential antiemetic regimen consisting of fosaprepitant, tropisetron, and dexamethasone, followed by aprepitant capsules, in the secondary prevention of moderate-to-severe chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients receiving epirubicin plus cyclophosphamide (EC regimen) chemotherapy. Methods A total of 106 breast cancer patients who received EC chemotherapy in Department of Oncology, the Affiliated Hospital of Xuzhou Medical University from March 2023 to March 2025 were enrolled. During the first chemotherapy cycle, all patients were treated with the traditional triple antiemetic regimen (fosaprepitant, tropisetron, and dexamethasone). Based on the control of nausea and vomiting during the first cycle, 31 patients who experienced moderate-to-severe CINV were selected as subjects (group A). In subsequent cycles, these patients received sequential aprepitant capsules in addition to the original regimen for secondary prevention (group B). The complete response rates during the acute phase, delayed phase, and overall phase, as well as the Functional Living Index–Emesis (FLIE) scores and adverse reactions, were compared before and after the intervention. Results Among the 106 patients receiving the EC regimen, the traditional triple antiemetic therapy showed limited efficacy in preventing CINV, particularly in controlling delayed-phase symptoms, although it was generally well tolerated with mild adverse events and no grade ≥3 toxicities. After adding sequential aprepitant capsules in 31 patients, the control of delayed-phase CINV improved significantly, with better efficacy for vomiting than for nausea. Both total FLIE scores and nausea/vomiting subscores improved significantly (P<0.05). There was no statistically significant difference in the incidence of adverse reactions between Groups A and B (P>0.05). Conclusions The sequential use of fosaprepitant, tropisetron, and dexamethasone followed by aprepitant capsules demonstrates good efficacy and tolerability in the secondary prevention of CINV in breast cancer patients receiving EC chemotherapy, particularly showing superiority in controlling delayed-phase CINV and improving patients’ quality of life, with controllable adverse reasctions. This sequential regimen can be considered an optimal strategy for the secondary prevention of CINV in breast cancer patients treated with the EC regimen.