BACKGROUND Spinal muscular atrophy (SMA) is a rare neuromuscular disease and the most common genetic cause of infant death. Although pharmacological treatment improves survival rates and functional capacity, physiotherapy remains a key component of care. A newly developed innovative equine-assisted physiotherapy method based on neuro-proprioceptive “facilitation and inhibition” principles (NEUROEQUIP-SMA), could potentially improve the quality and extent of motor development in children with SMA. OBJECTIVE The aim of the study is to compare NEUROEQUIP-SMA with standard physiotherapy and to evaluate its effect on functional outcomes and quality of life. In addition, the response of molecular biomarkers, such as long non-coding RNAs (lncRNAs), to treatment will be monitored. METHODS In this randomized, assessor-blinded controlled trial (NCT05341453), 16 children with SMA types I–III (aged 2–9 years) will be divided into two groups. Both groups will undergo a 6-day therapeutic program of equal duration and intensity. The intervention group will undergo NEUROEQUIP-SMA therapy, the control group will undergo standard physiotherapy, and both groups will undergo therapeutic grooming. Primary outcomes include motor coordination measured using 3D motion analysis, the presence of muscle fatigue (using surface EMG), spirometry, standardized tests and scaling tests. Secondary outcomes include monitoring of children's psychomotor development (home video analysis) and quality of life (the International Classification of Functioning, Disability and Health-based Documentation Form for the category "Children with Cerebral Palsy Brief”). LncRNAs will be analyzed from blood samples. Statistical analysis will be performed in R software. The study was approved by the Ethics Committee of the Third Faculty of Medicine, Charles University (ref.: 24.2.2022 and 6.3.2023). Informed consent was obtained from the legal representatives of the participants. RESULTS The study was initially designed for 8 participants. Data collection began in April 2022 and was completed in October 2024. Data analyses are planned for autumn 2025. Study results are expected to be available in 2026. The study is anticipated to be fully completed by the end of 2026. CONCLUSIONS This trial will be the first study to evaluate the effects of an equine-assisted physiotherapy intervention based on neuro-proprioceptive principles in children with SMA. If the intervention proves effective, it could expand physiotherapy options for this new generation of children receiving genetic therapies. It is also expected that the results of this study may contribute to the optimization of rehabilitation strategies that integrate biomechanical, clinical, and molecular perspectives. CLINICALTRIAL ClinicalTrials.gov NCT05341453; https://clinicaltrials.gov/study/NCT05341453.