Background: Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody–drug conjugate (ADC) with substantial activity across HER2-expressing breast cancer. Interstitial lung disease (ILD)/pneumonitis is its most important adverse event of special interest and can be fatal. We report an early-onset, oxygen-requiring case and systematically review the incidence, timing, presentation, and management of T-DXd–associated ILD in breast cancer. Case presentation: A 47-year-old woman with de novo ER-negative, PR-negative, HER2-positive metastatic breast cancer (hepatic, pulmonary, and osseous metastases) and hepatic visceral crisis (total bilirubin 375 µmol/L) started T-DXd on 28 June 2026. After two cycles, bilirubin fell to 113 µmol/L and then normalised, with multisite radiological response. Approximately 5 weeks after the first dose she developed dyspnoea, non-productive cough, low-grade fever, tachycardia, and hypoxaemia (SpO₂ ≈88% on room air). CT pulmonary angiography excluded embolism and showed new bilateral ground-glass and consolidative opacities with interlobular septal thickening, while pulmonary metastases were regressing. Bronchoalveolar lavage (BAL) was negative for malignancy, fungi, and Pneumocystis jirovecii. Grade 3 T-DXd–associated ILD was diagnosed; T-DXd was permanently discontinued and prednisolone (≈1 mg/kg/day) plus empirical piperacillin–tazobactam and supplemental oxygen were started, with clinical stabilisation. Methods: Following PRISMA 2020, we searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, Scopus, and major oncology congress proceedings to 31 October 2026 for prospective trials of T-DXd in breast cancer reporting ILD incidence and for case reports/series of T-DXd–associated ILD. Incidence was pooled with a DerSimonian–Laird random-effects model on the logit scale. Results: Eight prospective trials (3,341 T-DXd-treated patients) were pooled. Any-grade drug-related ILD occurred in 12.1% (95% CI 10.7–13.6; I² = 39%) and grade 5 ILD in 0.8% (95% CI 0.5–1.5). In metastatic disease the pooled incidence was 12.7% (11.4–14.0; I² = 0%); in HER2-positive metastatic disease, 13.1% (11.4–15.0). Case reports (7 patients) and national post-marketing data showed an organising-pneumonia–predominant imaging pattern, onset ranging from 2 to 9 cycles, frequent prolonged corticosteroid dependence, and use of cyclophosphamide, infliximab, mycophenolate, or tacrolimus in steroid-refractory cases. Conclusions: Roughly one in eight breast cancer patients receiving T-DXd develops ILD, and about 1% die of it. Onset can be early, and ILD can emerge during an excellent tumour response—discordant radiology (regressing nodules with new diffuse opacities) is a useful diagnostic clue. Structured respiratory surveillance, low threshold for CT, prompt exclusion of infection, permanent discontinuation for grade ≥2 events, and grade-appropriate corticosteroids remain central. Keywords: Trastuzumab deruxtecan; interstitial lung disease; pneumonitis; HER2-positive breast cancer; antibody–drug conjugate; visceral crisis; systematic review; meta-analysis.