Introduction <p>Trastuzumab deruxtecan (T-DXd) has recently reshaped the management of HER2-low metastatic breast cancer. While pivotal trials relied on CT-based RECIST 1.1, [¹⁸F]FDG PET/CT provides high diagnostic sensitivity and valuable semi-quantitative metrics, though its role in monitoring antibody–drug conjugates remains insufficiently defined. This study assessed the prognostic value of PET-derived parameters and PERCIST criteria in patients treated with T-DXd.</p> Methods <p>This retrospective study included all HER2-low metastatic breast cancer patients treated with T-DXd between 2022 and 2025 at the Strasbourg Europe Cancer Institute (ICANS) who underwent [¹⁸F]FDG PET/CT. Semi-quantitative parameters (SUVmax, SULpeak) and metabolic response according to PERCIST 1.0 were collected. Their association with overall survival (OS), metabolic progression-free survival (mPFS) and time-to-treatment change (TTT) was analyzed using Cox models and Kaplan–Meier curves.</p> Results <p>Forty-three patients were included. Baseline SULpeak of the most hypermetabolic lesion was an independent prognostic factor for OS, mPFS and TTT (<i>p &lt; 0.05</i>). A ROC-derived cutoff of 6 identified two prognostic groups, with SULpeak &lt; 6 associated with significantly improved outcomes. Early metabolic response was also linked to longer OS and PFS (<i>p&lt; 0.05</i>), with median PFS of 9.2 vs. 4.2 months (HR 2.67; 95% CI 1.30–5.47). Combining baseline SULpeak and metabolic response (complete or partial metabolic response) defined three risk groups with significantly different OS and PFS.</p> Conclusion <p>[¹⁸F]FDG PET/CT provides significant prognostic information in HER2-low metastatic breast cancer treated with T-DXd. Baseline SULpeak and early PERCIST response enable meaningful risk stratification. The proposed prognostic model requires prospective validation before clinical implementation.</p>