Introduction <p>There is a paucity of real-world evidence on the impact of early treatment as well as polytherapy use on advanced motor milestone achievement in children with spinal muscular atrophy (SMA) with ≤ 2 survival motor neuron 2 gene (<i>SMN2</i>) copies. The objective of this study is to evaluate predictors of motor milestone change in children with ≤ 2 <i>SMN2</i> copies, focusing on the timing of treatment initiation and the impact of treatment decisions.</p> Methods <p>This study employed a mixed longitudinal and repeated cross-sectional design. Data were drawn from the Cure SMA Community Update Survey, collected between 2020 and 2024. The study included 228 children with ≤ 2 <i>SMN2</i> copies, each contributing at least one survey response, resulting in 414 total observations collected over the study period, with data provided by caregivers who reported residence in the USA. The primary outcome was maximum motor milestone achievement, evaluated using a mixed-effects ordinal hierarchical regression model to account for individual variability and repeated measures.</p> Results <p>Treatment before 3 weeks of age increased the odds of greater motor milestone achievement by 13.4-fold compared to treatment after 4&#xa0;months (<i>p</i> = 0.001). SMA prenatal or newborn screening facilitated earlier treatment and reduced disparities in motor milestone achievement across income levels. Polytherapy was linked to 2.4-fold higher odds of reaching higher-level motor milestones compared to monotherapy (<i>p</i> = 0.01).</p> Conclusions <p>Early treatment initiation improved motor outcomes in children with ≤ 2 <i>SMN2</i> copies. The findings support the importance of screening newborn screening as part of an effective strategy for optimizing motor development, as well as support the importance of further investigation into the relationship between the increasing proportion of polytherapy use and motor function development.</p>