Practicing a musical instrument has a profound impact on the structure and function of the human brain. The present fMRI study explored how relative hemispheric asymmetries in task-related activity during music processing (same/different discrimination) are shaped by musical training (quantified as cumulative hours of instrument practice), using both a large (N = 84) cross-sectional data set of children and adults, and a smaller (N = 20) two time-point longitudinal data set of children tracked over 3 to 5 years. The cross-sectional analysis revealed a significant leftward asymmetry in task-related activation, with peaks in Heschl's gyrus and supramarginal gyrus (SMG). The SMG peak was further characterized by a leftward asymmetry in the partial correlation strength with subjects' cumulative hours of practice, controlling for subjects' age and task performance. This SMG peak was found to exhibit a similar pattern of response in the longitudinal data set (in this case, with subjects' cumulative hours of practice over the course of the study), controlling for age, scan interval, and amount of instrument practice prior to the first scan. This study presents novel insights into the ways musical instrument training shapes task-related asymmetries in neural activity during music processing.