Trastuzumab deruxtecan (T-DXd) is the current standard second-line therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it has been recently approved by FDA as first line therapy in combination with pertuzumab, following the results of the DESTINY-Breast09 trial. However, optimal treatment strategies following T-DXd remain undefined and data on subsequent therapies are limited. The present study evaluated the efficacy of combined treatment with tucatinib, trastuzumab, and capecitabine (TTC) after T-DXd. Patients with HER2-positive MBC who received TTC as second- or third-line therapy following T-DXd in the 17 participating centers were eligible. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were time to next treatment, overall survival (OS), and objective response rate. Between July 2021 and June 2025, 105 patients who received TTC as second- or third-line therapy following T-DXd were included in the study. The median age was 55.1 years, 41.0% had de novo metastatic disease, and 55.2% had brain metastases. Most patients (91.4%) received TTC as third-line therapy. During a median follow-up of 19.5 months, the median PFS, time to next treatment, and OS were 4.7, 6.6, and 15.3 months, respectively. Among evaluable patients, the objective response rate was 29.6%, with 9.2% achieving complete response. Patients with prior T-DXd exposure for >18 months had improved PFS (6.0 months) compared to those with prior T-DXd exposure for ≤18 months (3.8 months). TTC exhibited clinically meaningful activity following T-DXd in patients with HER2-positive MBC, particularly those with prolonged T-DXd response.