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Introduction Spinal cord injury (SCI) frequently results in severe neurological impairment due to neural tissue destruction and scarring, representing a substantial and increasing global health burden. Current standard treatments primarily focus on preventing secondary complications but offer limited efficacy in repairing neural circuits or reversing neurological deficits. Stem cell transplantation, particularly using induced pluripotent stem cell (iPSC)-derived therapies, presents a regenerative strategy that avoids the ethical constraints associated with embryonic stem cells while providing a scalable source for cellular therapeutics. Specifically, allogeneic, ‘off-the-shelf’ iPSC-derived motor neuron progenitors offer a standardised and scalable approach, supported by a dual therapeutic mechanism observed in preclinical models.Methods and analysis This is a prospective, multicentre, open-label, single-arm clinical study involving 12–24 adult patients with subacute SCI. To evaluate safety and tolerability, the trial is structured into sequential Single Ascending Dose (SAD; n=6–12) and Multiple Ascending Dose (MAD; n=6–12) phases. Both phases employ a standard ‘3+3’ dose-escalation design across two dose levels (level 1: 5×10⁷ cells/dose; level 2: 1.5×10⁸ cells/dose). Participants in the SAD phase receive a single intrathecal administration, whereas those in the MAD phase receive four biweekly intrathecal administrations. Dose escalation, cohort expansion and progression from the SAD to the MAD phase are strictly contingent on the absence of dose-limiting toxicities (DLTs) over a 28-day observation window following the single dose (SAD) or the final dose (MAD). The primary endpoint is to determine the incidence of treatment-related adverse events (AEs) and serious AEs, identify DLTs and establish the maximum tolerated dose as well as the recommended phase II dose. Efficacy will be assessed by evaluating longitudinal changes in American Spinal Injury Association (ASIA) Impairment Scale grade, American Spinal Injury Association (ASIA) sensory/motor scores and Spinal Cord Independence Measure score at predefined follow-up visits (days 29, 71, 90, 180, 270 and 360) up to 360 days post-baseline. Exploratory objectives include characterising the potential therapeutic mechanisms and broader clinical impact through longitudinal assessment of cerebrospinal fluid biomarkers, neurophysiological function, bladder outcomes and spinal cord imaging metrics.Ethics and dissemination The study protocol has received ethical approval from the Institutional Ethics Committees of the Third Affiliated Hospital of Sun Yat-sen University (Approval No. YW2025-012-01) and the Third Hospital of Hebei Medical University (Approval No. 2025–071-2). Furthermore, the investigational product has secured regulatory clearance for clinical trials from both the China National Medical Products Administration (Clinical Trial Notification No. 2025LP01101) and the US Food and Drug Administration (IND No. 31234). Written informed consent will be obtained from all participants before participation. Moreover, strict adherence will be maintained to the Declaration of Helsinki and Good Clinical Practice guidelines throughout the study. To ensure transparency and broad dissemination, the study results will be disseminated through peer-reviewed publications and conference presentations.Trial registration number NCT06976229.