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Introduction Bronchopulmonary dysplasia (BPD) remains a major complication among extremely low gestational age (ELGA) infants, with long-term respiratory and neurodevelopmental consequences. Despite advances in neonatal care, effective therapies to prevent BPD are lacking. Mesenchymal stromal cells (MSCs), particularly those derived from umbilical cord (UC-MSC), offer promise due to their pleiotropic effects. Preclinical and early-phase clinical studies have demonstrated safety and potential efficacy of MSC in neonatal lung injury. The Helping Underdeveloped Lungs with Cells (HULC)-2 trial aims to evaluate whether multiple intravenous doses of human allogenic UC-MSC can reduce mechanical ventilation duration and improve the respiratory outcome in ELGA infants at high risk of developing BPD.Methods and analysis HULC-2 is a multicentre, double-blind, randomised controlled Phase II trial conducted in Canadian Neonatal Intensive Care Units. ELGA infants (gestational age <28 weeks) who remain ventilator-dependent between 4 and 14 days of life will be randomised to receive either 3 weekly intravenous doses of UC-MSC (10×10 6 cells/kg/dose) or a sham procedure. The primary outcome is ventilation-free days (VFDs) at 120 days postrandomisation, accounting for mortality. Secondary outcomes include cell administration safety, respiratory and neurodevelopmental outcomes and complications of prematurity. A total of 168 participants will be enrolled to detect a clinically meaningful difference in VFDs.Ethics and dissemination The study was approved through Clinical Trials Ontario by the Ottawa Health Science Network Research Ethics Board. Results will be disseminated via peer-reviewed publications, conferences and public engagement platforms. Parent partners are actively involved in study design and dissemination to ensure relevance and transparency.Trial registration number NCT07058025.