Background: The patient’s neuro-respiratory drive, measured as electrical activity of the diaphragm (EAdi), quantifies the mechanical load on the respiratory muscles. It correlates with respiratory effort but requires a dedicated esophageal catheter. Transcutaneous (surface) monitoring of respiratory muscle electromyographic (sEMG) signals may be considered a suitable alternative to EAdi because of its non-invasive character, with the additional benefit that it allows for simultaneously monitoring of other respiratory muscles. We therefore sought to study the neuro-respiratory drive and timing of inspiratory muscles using sEMG in a cohort of children enrolled in a pediatric ventilation liberation trial. The neuro-mechanical coupling, relating the pressure generated by the inspiratory muscles to the sEMG signals of these muscles, was also calculated. Methods: This is a secondary analysis of data from a randomized cross-over trial in ventilated patients aged < 5 years. sEMG recordings of the diaphragm and parasternal intercostal muscles (ICM), esophageal pressure tracings and ventilator scalars were simultaneously recorded during continuous spontaneous ventilation and pressure controlled-intermittent mandatory ventilation, and at three levels of pressure support. Neuro-respiratory drive, timing of diaphragm and ICM relative to the mechanical ventilator’s inspiration and neuro-mechanical coupling were quantified. Results: Twenty-nine patients were included (median age: 5.9 months). In response to decreasing pressure support, both amplitude of sEMG (diaphragm: p = 0.001 and ICM: p = 0.002) and neuro-mechanical efficiency indices increased (diaphragm: p = 0.05 and ICM: p < 0.001). Poor correlations between neuro-respiratory drive and respiratory effort were found, with R2: 0.088 [0.021–0.152]. Conclusions: sEMG allows for the quantification of the electrical activity of the diaphragm and ICM in mechanically ventilated children. Both neuro-respiratory drive and neuro-mechanical efficiency increased in response to lower inspiratory assistance. There was poor correlation between neuro-respiratory drive and respiratory effort. Trial registration: ClinicalTrials.gov ID NCT05254691. Registered 24 February 2022, registered retrospectively.