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Rationale: Trophoblast cell-surface antigen 2 (Trop2) is an essential therapeutic target in breast cancer, yet non-invasive methods for assessing its expression and predicting response to Trop2-directed antibody-drug conjugates (ADCs) remain limited. We aimed to evaluate the diagnostic accuracy of ⁶⁸Ga-MY6349 positron emission tomography/computed tomography (PET/CT) in patients with breast cancer and assess its impact on clinical decision-making. Methods: We prospectively enrolled 73 patients with suspected or confirmed breast cancer who underwent both ⁶⁸Ga-MY6349 and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT from December 2024 to April 2025. Lesion-based diagnostic performance was compared using histopathology and follow-up imaging as reference standards. Treatment decisions were recorded before and after ⁶⁸Ga-MY6349 PET/CT. Serial ⁶⁸Ga-MY6349 PET/CT was performed to assess the early metabolic response in three patients with triple-negative breast cancer receiving sacituzumab tirumotecan. Results: ⁶⁸Ga-MY6349 PET/CT identified more malignant lesions (564 vs. 436) and fewer false positives (2 vs. 40) than ¹⁸F-FDG PET/CT. In the initial-staging cohort (n = 30), ⁶⁸Ga-MY6349 PET/CT led to TNM stage upgrades in 6/30 patients (20%) and treatment modifications in 4/30. In the restaging cohort (n = 43), clinical management was altered in 5/43 patients (12%) owing to the identification of additional metastatic lesions or rectification of false-positive findings via ⁶⁸Ga-MY6349 PET/CT. ⁶⁸Ga-MY6349 PET/CT yielded higher overall tumor uptake (median maximum standardized uptake value (SUV_max), 5.9 vs. 4.1; P < 0.001) and improved lesion conspicuity, particularly in lymph node and metastatic lesions. Exploratory analysis in three patients receiving Trop2-ADC therapy showed that early changes in ⁶⁸Ga-MY6349 uptake after two treatment cycles were concordant with the subsequent clinical response. Conclusions: ⁶⁸Ga-MY6349 PET/CT demonstrated superior diagnostic performance to ¹⁸F-FDG PET/CT in breast cancer staging and diagnosis, directly influencing therapeutic strategies. Preliminary findings from the triple-negative breast cancer cases suggest that early changes in SUV_max may be associated with the treatment response to Trop2-targeted ADC therapy, warranting further prospective validation in larger patient populations.