This longitudinal study investigated monthly motor development and physical activity (PA) of infants with and without Down syndrome. Gross and fine motor skills (Bayley Scales of Infant Development-III) and PA (accelerometer) were assessed in 35 infants at eight time points during infancy. A multivariate mixed model identified time points when motor scores diverged between the groups. In infants with Down syndrome, bivariate correlations between monthly PA and motor changes were calculated, and multivariate analysis of variance probed the influence of early PA on motor-skill timing. Results indicate that differences in gross and fine motor skills first emerge at 2 and 4 months, respectively. In infants with Down syndrome, gross motor and PA changes between 4 and 6 months were positively correlated. Infants more active than the mean at 2 or 3 months achieved several prone and sitting skills earlier. These results highlight the adaptability of early infancy and the importance of early intervention.